Modifications of Porphyrins and Hydroporphyrins for Their

molecules

Review Modiﬁcations of Porphyrins and Hydroporphyrins for Their Solubilization in Aqueous Media

Michael Luciano and Christian Brückner *

Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-860-486-2743

Received: 19 May 2017; Accepted: 9 June 2017; Published: 13 June 2017

Abstract: The increasing popularity of porphyrins and hydroporphyrins for use in a variety of biomedical (photodynamic therapy, ﬂuorescence tagging and imaging, photoacoustic imaging) and technical (chemosensing, catalysis, light harvesting) applications is also associated with the growing number of methodologies that enable their solubilization in aqueous media. Natively, the vast majority of synthetic porphyrinic compounds are not water-soluble. Moreover, any water-solubility imposes several restrictions on the synthetic chemist on when to install solubilizing groups in the synthetic sequence, and how to isolate and purify these compounds. This review summarizes the chemical modiﬁcations to render synthetic porphyrins water-soluble, with a focus on the work disclosed since 2000. Where available, practical data such as solubility, indicators for the degree of aggregation, and special notes for the practitioner are listed. We hope that this review will guide synthetic chemists through the many strategies known to make porphyrins and hydroporphyrins water soluble.

Keywords: water-solubility; porphyrin; chlorin; bacteriochlorin; PEGylation; bioconjugation; photodynamic therapy; bioimaging

1. Introduction The utility of porphyrins and hydroporphyrins (chlorins and bacteriochlorins) in a variety of biomedical applications has been demonstrated [1]. These include photodynamic cancer therapy [2–5], antifungal photodynamic therapy [6], their use as photoantimicrobials [7], as fluorescence and photo-acoustic imaging agents [5,8–14], (single) cell imaging [15] and fluorescence labelling [16], and as in vivo chemosensors [17,18]. In addition, they have shown value in a number of technical applications, such as chemosensing [17], electronic devices and materials [19–21], catalysis [22], photocatalysis [23,24], and light harvesting [25–28]. These applications rest on the favorable optical, chemical and electronic properties of these porphyrinoids: their intense absorbance in the visible to near infrared (NIR) region, high fluorescence or singlet oxygen quantum yields, good photoacoustic signal generation efficiency, ease of ejection of a photo-excited electron, etc. Many of these applications would greatly benefit from an inherent solubility of the porphyrins in aqueous media, i.e., not requiring any surfactants or liposome vesicles to mediate solubility. However, even though the methodologies for preparing synthetic porphyrins [29,30], hydroporphyrins [2,31–34], and their analogues [34–39], have advanced enormously in the past decades, the vast majority of the synthetic porphyrinoids presented are not natively water-soluble, preventing—or at least complicating—their utilization in, for example, biological contexts. Initial efforts to impart water-solubility relied on the utilization of meso-pyridyl and meso-p-sulfonatophenyl-substituents in (mostly) symmetric porphyrins. These porphyrins were based on Adler syntheses of tetrapyridyl- and tetraphenylporphyrin, followed by quarternization with a suitable alkyl halide or direct sulfonation, respectively. Albeit simple, both methods have drawbacks.

Molecules 2017, 22, 980; doi:10.3390/molecules22060980 www.mdpi.com/journal/molecules Molecules 2017, 22, 980 2 of 47

Molecules 2017, 22, 980 2 of 46 They are difficult to translate to β-alkyl-substituted porphyrins, the sulfonation reaction conditions are difficult to translate to β-alkyl-substituted porphyrins, the sulfonation reaction conditions are are harsh and therefore incompatible with many hydroporphyrin chromophores or substituents that harsh and therefore incompatible with many hydroporphyrin chromophores or substituents that convey desirable properties onto the porphyrin. This led to the development of a range of alternative convey desirable properties onto the porphyrin. This led to the development of a range of alternative methods to impart water-solubility that are mild, selective, and that generate the water-soluble methods to impart water-solubility that are mild, selective, and that generate the water-soluble porphyrin derivative late in the synthetic sequence, thus facilitating its isolation and purification. porphyrin derivative late in the synthetic sequence, thus facilitating its isolation and purification. Rather than attempting to be comprehensive, we aim to present here a tutorial-style review that Rather than attempting to be comprehensive, we aim to present here a tutorial-style review that highlights recent (since ~2000) synthetic strategies. Where data are available, we compare the resulting highlights recent (since ~2000) synthetic strategies. Where data are available, we compare the resulting solubilities, and report on other notable practical considerations. This summary extends a review solubilities, and report on other notable practical considerations. This summary extends a review on on water-soluble porphyrins published in the year 2000 [40] that provides a detailed account of the water-soluble porphyrins published in the year 2000 [40] that provides a detailed account of the acid- acid-base properties and aggregation behavior of conventional water-soluble porphyrins. A 2014 base properties and aggregation behavior of conventional water-soluble porphyrins. A 2014 review review on amphiphilic porphyrins by Gryko and co-workers [41] is also available; overlap with on amphiphilic porphyrins by Gryko and co-workers [41] is also available; overlap with this review this review is minimized and these reviews are thus complementary. Porphyrins linked to sugars, is minimized and these reviews are thus complementary. Porphyrins linked to sugars, many of which manyare also of whichwater-soluble, are also have water-soluble, been reported have [ been41–43]. reported We chose [41 –not43]. to We include chose notthem to here include because them hereglycosylation because glycosylationstrategies are frequently strategies not are driven frequently by achieving not driven water-solubility by achieving but water-solubility to increase tumor but totargeting; increase they tumor were targeting; also reviewed they were in alsothe cont reviewedext of inamphiphilic the context porphyrins of amphiphilic [41]. porphyrinsWater-soluble [41 ]. Water-solubleporphyrins conjugated porphyrins conjugatedto biomolecules to biomolecules (e.g., oligonucleotides (e.g., oligonucleotides and peptides), and peptides), appended appended to tofunctionalities functionalities such such as as cyclodextrans cyclodextrans [44], [44 ],crown crown et ethershers [45,46], [45,46 ],porphyrin porphyrin nanoparticles nanoparticles [47–50], [47–50 ],or or porphyrinsporphyrins thatthat werewere solubilizedsolubilized with the help of of surfactants surfactants or or vesicles vesicles [51–53] [51–53 ]are are also also beyond beyond the the scopescope ofof thisthis discussion.discussion. Likewise, we do do not not cover cover the the solubilization solubilization of of expa expandednded porphyrins porphyrins or or most most otherother porphyrinoids.porphyrinoids. TheThe reviewreview isis organizedorganized alongalong thethe chargecharge thethe solubilizationsolubilization groupsgroups introduce:introduce: Cationic Cationic (amine/ammonium,(amine/ammonium, pyridyl/pyridinium), pyridyl/pyridinium), anionic (sulfo anionicnate, phosphonate, (sulfonate, carboxylic phosphonate, acid/carboxylate) carboxylic acid/carboxylate)and neutral (polyethylene and neutral glycol (polyethylene (PEG) chains). glycol Each (PEG) section chains). discusses Each the sectionexamples discusses loosely in the examplesincreasing loosely order of in complexity increasing orderand the of position complexity of the and solubilizing the position group. of the Three solubilizing principle group. strategies Three principlefor the introduction strategies forof solubilizing the introduction groupsof can solubilizing be distinguished groups (Scheme can be 1). distinguished Strategy A encompasses (Scheme1). Strategythe synthesis A encompasses of a porphyrin the macrocycle synthesis using of a porphyrin building blocks macrocycle bearing usingsolubilizing building groups blocks (protected bearing solubilizingor not). Strategy groups B involves (protected the orsynthesis not). Strategy of a porphyrin B involves ma thecrocycle synthesis with ofprecursor a porphyrin functionalities, macrocycle withthat precursorcan later be functionalities, manipulated thatto hydrophilic can later be groups. manipulated Strategy to hydrophilicC employs synthetic groups. Strategy modifications C employs of synthetican already-formed modifications porphyrin of an already-formed to impart water porphyrinsolubility. to impart water solubility.

Strategy A: = solubilizing group

N N deprotection N N = protecting group building blocks N N = synthetic handle – N N

Strategy B:

functional group N N interconversion N N building blocks N N N N

Strategy C:

N N N N functionalization N N or N N N N N N

SchemeScheme 1. Principle strategies toward toward hydrophilic hydrophilic porphyrin porphyrin derivatives. derivatives.

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2. Water-Soluble Porphyrins Bearing Cationic Substituents Cationic porphyrins were among the first synthetic water-soluble porphyrins to be discovered [54]. TheseMolecules early 2017 methods, 22, 980 of solubilization relied on the N-alkylation of meso-tetrapyridylporphyrins3 of 46 and their metal complexes (see also Section 2.2.1)[41]. These types of cationic porphyrins were 2. Water-Soluble Porphyrins Bearing Cationic Substituents widely studied for their association with the polyanion DNA [55,56], as part of the quest for new photosensitizersCationic forporphyrins photodynamic were among therapy the first (PDT),synthetic and water-soluble for their porp promisehyrins asto be photoantimicrobials discovered [54]. These early methods of solubilization relied on the N-alkylation of meso-tetrapyridylporphyrins and for gram positive and gram negative bacteria [57]. Tetra-pyridyl/pyridiniumporphyrins are also their metal complexes (see also Section 2.2.1) [41]. These types of cationic porphyrins were widely commercially available [58]. studied for their association with the polyanion DNA [55,56], as part of the quest for new photosensitizers for photodynamic therapy (PDT), and for their promise as photoantimicrobials for gram positive and 2.1. Amine/Ammonium Functionalized Porphyrins gram negative bacteria [57]. Tetra-pyridyl/pyridiniumporphyrins are also commercially available [58]. One possibility for the preparation of cationic water-soluble porphyrins and hydroporphyrins is through2.1. derivatizationAmine/Ammonium with Functionalized amines or polyamines.Porphyrins Porphyrinoids with amine functional groups may be solubleOne in aqueous possibility media for the at preparation low pH, but of quarternizationcationic water-soluble of the porphyri aminesns with and suitablehydroporphyrins electrophiles is frequentlyis through employed derivatization to furnishwith amines freely or water-solublepolyamines. Porphyrinoids derivatives. with The amine resulting functional (poly)cationic groups derivativesmay be soluble are usually in aqueous purified media at by low crystallization pH, but quarternization protocols of the or amines reverse with phase suitable chromatography. electrophiles Ion-exchangeis frequently chromatography employed to furnish offers freely an option water-soluble to subsequently derivatives. exchange The resulting the halide (poly)cationic counter ion derivatives are usually purified by crystallization protocols or reverse phase chromatography. Ion- (typically Br− or I−) to another anion [59]. exchange chromatography offers an option to subsequently exchange the halide counter ion A number of symmetric and asymmetric amphiphilic meso-aryl porphyrins bearing amine (typically Br− or I−) to another anion [59]. functionalA groupsnumber have of symmetric been reported and asymmetric [41]. The amphiphilic strategies towardmeso-aryl their porphyrins generation bearing often amine rely on Adlerfunctional or Lindsey groups porphyrin have been syntheses reported incorporating[41]. The strategies amine-containing toward their generation building often blocks, rely on or Adler through modificationor Lindsey of otherporphyrin functionalities, syntheses suchincorporating as phenols. amine-containing building blocks, or through Krauszmodification and of co-workers, other function foralities, example, such as synthesized phenols. polyamine-meso-arylporphyrin conjugates by DCC-mediatedKrausz and amide-coupling co-workers, for example, of carboxylic synthesized acid-functionalized polyamine-meso-arylporphyrin A3B porphyrin conjugates2, made by by functionalizationDCC-mediated of amide-coupling phenol 1 with of di-Boc-protected-spermidinecarboxylic acid-functionalized A or3B tri-Boc-protected-spermineporphyrin 2, made by functionalization of phenol 1 with di-Boc-protected-spermidine or tri-Boc-protected-spermine (Scheme2)[ 60]. The ultimate starting A3B porphyrin 1 was synthesized using a mixed aldehyde (Scheme 2) [60]. The ultimate starting A3B porphyrin 1 was synthesized using a mixed aldehyde Adler Adler condensation, followed by alkylation of the phenolic oxygen with ethyl 4-bromobutanoate condensation, followed by alkylation of the phenolic oxygen with ethyl 4-bromobutanoate and and saponification. The thus generated polyamines were submitted to standard Boc-deprotection saponification. The thus generated polyamines were submitted to standard Boc-deprotection conditionsconditions to afford to afford the the polyamine-porphyrin polyamine-porphyrin conjugates conjugates 3 and 44, ,respectively. respectively.

Scheme 2. Spermine- and spermidine-porphyrin conjugates, as described by the group of Krausz [60]. Scheme 2. Spermine- and spermidine-porphyrin conjugates, as described by the group of Krausz [60]. DCC = dicyclohexylcarbodiimide, HOBt = 1-hydroxybenzotriazole. DCC = dicyclohexylcarbodiimide, HOBt = 1-hydroxybenzotriazole. Bacteriochlorins derived from natural sources and bearing an anhydride functionality could also Bacteriochlorinsbe derivatized by derivedamide formation from natural with polyamines sources and [61]. bearing Sol and an co-workers anhydride prepared functionality water-soluble could also be derivatizedchlorin polyamine by amide derivative formation 6 withthrough polyamines amidation [ 61of]. aSol chlorin and co-workersextracted from prepared Spirulina water-soluble maxima chlorin(Scheme polyamine 3). The polyamine derivative groups6 through were introduced amidation by of nucleophilic a chlorin ring extracted opening from of anhydrideSpirulina 5 with maxima polyethyleneimine (PEI, MW 600 Da). Alternatively, polyamination was performed at the propionic (Scheme3). The polyamine groups were introduced by nucleophilic ring opening of anhydride acid side chain. The anhydride moiety in chlorin 5 was first converted to an acetate-protected 5 with polyethyleneimine (PEI, MW 600 Da). Alternatively, polyamination was performed at the cycloimide chlorin 7 by treatment with hydroxylamine, followed by acylation. The subsequent

Molecules 2017, 22, 980 4 of 47 propionic acid side chain. The anhydride moiety in chlorin 5 was ﬁrst converted to an acetate-protected cycloimideMolecules chlorin 2017, 22,7 980by treatment with hydroxylamine, followed by acylation. The4 subsequent of 46 polyamination at the propionic acid side chain required activation of the carboxylic acid moiety, followedpolyamination by reaction at with the propionic PEI. In a acid similar side fashion,chain requ water-solubleired activation of polyaminated the carboxylic bacteriochlorinsacid moiety, 9 and 10 wereMoleculesfollowed prepared 2017 by, 22 reaction, 980starting with PEI. from In bacteriochlorins a similar fashion, water-soluble extracted from polyaminatedRhodobacter bacteriochlorins spaeroides4 of. 46 In9 water, and 10 were prepared starting from bacteriochlorins extracted from Rhodobacter spaeroides. In water, the resulting compounds exhibited split and/or broadened Soret bands, indicating some degree polyaminationthe resulting compounds at the propionic exhibited acid split side and/or chain brrequoadenedired activation Soret bands, of the indicating carboxylic some acid degree moiety, of of aggregation.followedaggregation. by reaction with PEI. In a similar fashion, water-soluble polyaminated bacteriochlorins 9 and 10 were prepared starting from bacteriochlorins extracted from Rhodobacter spaeroides. In water, the resulting compounds exhibited split and/or broadened Soret bands, indicating some degree of aggregation.

Scheme 3. Chlorin and bacteriochlorin polyamines derived from Spirulina maxima and Rhodobacter Scheme 3. Chlorin and bacteriochlorin polyamines derived from Spirulina maxima and Rhodobacter spaeroides, respectively, as described by the group of Sol [61]. PEI = polyethyleneimine (PEI, MW 600 Da),

spaeroidesHBTU, respectively, = (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium as described by the group of Sol hexa [61].fluorophosphate), PEI = polyethyleneimine DIPEA = N,N- (PEI, MW 600Schemediisopropylethylamine. Da), HBTU 3. Chlorin = (2-(1 andH bacteriochlorin-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium polyamines derived from Spirulina maxima hexafluorophosphate), and Rhodobacter DIPEA =spaeroidesN,N-diisopropylethylamine., respectively, as described by the group of Sol [61]. PEI = polyethyleneimine (PEI, MW 600 Da), HBTUAmine = groups (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium were also introduced to porphyrins bearing hexa carboxylicfluorophosphate), acid groups DIPEA by esterification = N,N- withdiisopropylethylamine. an amino-alcohol. An example of this strategy was the preparation of a tricationic water-soluble Amineester groupsof chlorin were e6 11 also (Scheme introduced 4) [62]. Methyl to porphyrins pheophorbide bearing a was carboxylic saponified, acid and groupsthe acid bygroups esterification in with anproduct amino-alcohol.Amine 11 groupswere Anactivatedwere example also asintroduced acid of thischlorides to strategy porphyrins andwas esterified bearing the preparation carboxylicwith N,N acid-dimethylamino-ethanol of gr aoups tricationic by esterification water-soluble to with an amino-alcohol. An example of this strategy was the preparation of a tricationic water-soluble ester ofprovide chlorin triamine e6 11 (Scheme 12. Quarternization4)[ 62]. Methyl by reaction pheophorbide with CH3I gavea thewas tricationic saponified, water-soluble and the chlorin acid groups ester of chlorin e6 11 (Scheme 4) [62]. Methyl pheophorbide a was saponified, and the acid groups in in productderivative11 were 13 [62]. activated as acid chlorides and esterified with N,N-dimethylamino-ethanol to product 11 were activated as acid chlorides and esterified with N,N-dimethylamino-ethanol to provideprovide triamine triamine12. Quarternization 12. Quarternization by by reaction reaction withwith CH CH3I3 gaveI gave the the tricationic tricationic water-soluble water-soluble chlorin chlorin derivativederivative13 [62 ].13 [62].

Scheme 4. Cationic esters of chlorin e6 with terminal ammonium groups, as described by the group of Inoue [62].

Scheme 4. Cationic esters of chlorin e6 with terminal ammonium groups, as described by the group SchemeAmine 4. Cationic groups esters have of been chlorin introduced e6 with to terminal the β-positions ammonium of hydroporphyrins groups, as described by transition by the metal- group of mediatedof Inoue coupling [62]. strategies using β-bromo precursors. Thus, Lindsey and co-workers prepared a Inoue [62].

Amine groups have been introduced to the β-positions of hydroporphyrins by transition metal- Aminemediated groups coupling have strategies been introducedusing β-bromo to precursors. the β-positions Thus, Lindsey of hydroporphyrins and co-workers prepared by transition a metal-mediated coupling strategies using β-bromo precursors. Thus, Lindsey and co-workers

Molecules 2017, 22, 980 5 of 47

preparedMolecules a 2017 range, 22, 980 of water-soluble cationic bacteriochlorin derivatives utilizing the5 of versatile 46 3,13-dibromo-bacteriochlorin building block 14. The bromo groups are susceptible to a variety of transitionrange of metal-mediated water-soluble cationic C-C bondbacteriochlorin forming couplingderivatives reactions utilizing the (Scheme versatile5)[ 3,13-dibromo-63]. For example, bacteriochlorinsbacteriochlorin15a building–15c were block prepared 14. The bromo from groups14 through are susceptible a carbonylation to a variety→ ofacid transition chloride metal- reaction with secondarymediated C-C amines. bond forming Additionally, coupling reactions reaction (Scheme of amide5) [63]. For salts example, with bacteriochlorins14 in a carbonylation 15a–15c → were prepared from 14 through a carbonylation → acid chloride reaction with secondary amines. amidation sequence gave the aminobacteriochlorins 16a and 16b. Sonogashira coupling of 14 with Additionally, reaction of amide salts with 14 in a carbonylation → amidation sequence gave the an ethynyl-amine,aminobacteriochlorins followed 16a by and reduction 16b. Sonogashira gave the coupling bacteriochlorin of 14 with an17 ethynyl-amine,with amine-terminated followed by alkyl chains.reduction Lastly, a gave variety the of bacteriochlorin secondary amines 17 with were amine-terminated employed in a βalkyl-formylation chains. Lastly,→ reductive-amination a variety of strategysecondary to produce amines amine-functionalized were employed in a β-formylation bacteriochlorins → reductive-amination18a–18e. The strategy resulting to produce amines were amenableamine-functionalized to puriﬁcation bybacteriochlorins silica gel column 18a–18e chromatography. The resulting amines (EtOAc were or amenable CH2Cl 2to/MeOH/NH purification 4OH as eluents).by silica Subsequent gel columnN chromatography-alkylation of the (EtOAc amines or CH was2Cl achieved2/MeOH/NH using4OH standard as eluents). conditions, Subsequent and the N-alkylation of the amines was achieved using standard conditions, and the water-soluble cationic water-soluble cationic products that precipitated from the CHCl3 reaction mixtures were isolated by products that precipitated from the CHCl3 reaction mixtures were isolated by precipitation and precipitation and centrifugation. Some of these compounds were investigated for their efﬁcacy as centrifugation. Some of these compounds were investigated for their efficacy as antimicrobial antimicrobialphotosensitizers photosensitizers [64]. [64].

SchemeScheme 5. β-substituted 5. β-substituted cationic cationic ammonium ammonium bacteriochlorin bacteriochlorin derivatives, as as described described by bythe thegroup group of of Lindsey [63]. DCE = dichloroethane. Lindsey [63]. DCE = dichloroethane. Lindsey and co-workers also used similar dibromobacteriochlorin 19 to directly introduce Lindseyarylamines and to the co-workers β-positions also via Suzuki used similarcouplings dibromobacteriochlorin (Scheme 6) [65]. After the coupling19 to directly of dibromo- introduce arylaminesbacteriochlorin to the 19β-positions with an aryl via boronic Suzuki estercouplings bearing two (Scheme Boc-protected6)[ 65amines,]. After the Boc the groups coupling in of dibromo-bacteriochlorin 19 with an aryl boronic ester bearing two Boc-protected amines, the Boc groups in product 20 were removed, and the free amine quarternized by treatment with CH3I to afford the ﬁnal ammonium-functionalized bacteriochlorin product 21. Molecules 2017, 22, 980 6 of 46

Moleculesproduct2017, 2220, were 980 removed, and the free amine quarternized by treatment with CH3I to afford the final 6 of 47 ammonium-functionalized bacteriochlorin product 21.

Molecules 2017, 22, 980 6 of 46

product 20 were removed, and the free amine quarternized by treatment with CH3I to afford the final ammonium-functionalized bacteriochlorin product 21.

Scheme 6. β-Substituted cationic ammonium bacteriochlorin derivatives prepared by Suzuki coupling, as Scheme 6. β-Substituted cationic ammonium bacteriochlorin derivatives prepared by Suzuki coupling, described by the group of Lindsey [65]. as described by the group of Lindsey [65]. Related compounds with terminal amine functional groups, such as 3,13-diaryl bacteriochlorin 22, wereRelated prepared compounds using withsimilar terminal Suzuki aminecoupling functional strategies. groups, Bioconjugatable such as 3,13-diaryl derivatives bacteriochlorin of these 22, werecompounds prepared carrying using an similar NHS-ester Suzuki functional coupling group, strategies. such as 23 Bioconjugatable, were also prepared derivatives by a regio- of these compoundsselective carrying meso-bromination an NHS-ester → Suzuki functional coupling group, sequence such (see as 23 also, were Section also 2.2.2) prepared [65]. by a regio-selective meso-brominationTheScheme group 6. β→ -Substitutedof SuzukiLindsey couplingcationicalso prepared ammonium sequence a range bacteriochlorin (see of amphiphilic also Sectionderivatives bacteriochlorins 2.2.2 prepared)[65 ].by Suzuki of limited coupling, aqueous as solubility bearing one amine side chain by reductive amination of a β-formylated bacteriochlorin (see The groupdescribed of by Lindsey the group also of Lindsey prepared [65]. a range of amphiphilic bacteriochlorins of limited aqueous also Scheme 5) [66]. A representative example is bacteriochlorin 24, which possesses an ammonium- β solubilityterminatedRelated bearing dialkyl compounds one chain, amine witha so-called side terminal chain swallowtail amine by reductive functional functionality. aminationgroups, Thissuch ofmoiety as a 3,13-diaryl-formylated was designed bacteriochlorin bacteriochlorin to project 22 , (seesolubilizing alsowere Schemeprepared groups5 )[using above66 ].similar and A belo representativeSuzukiw the couplingplane of example thestrategies. macrocycle, is Bioconjugatable bacteriochlorin leading to facial derivatives 24encumbrance, which of possessesthese that an ammonium-terminatedinhibitscompounds macrocycle carrying stacking an dialkylNHS-ester and increases chain, functional ahydrop so-called group,hilicity. swallowtailsuch A similaras 23, werestrategy functionality. also was prepared used This to by solubilize moietya regio- was designedmesoselective-aryl to project mesoporphyrins-bromination solubilizing in orga →nic groups Suzuki solvents abovecoupling [67,68]. and sequence below the(see planealso Section of the 2.2.2) macrocycle, [65]. leading to facial encumbranceThe group that inhibits of Lindsey macrocycle also prepared stacking a range and of amphiphilic increases hydrophilicity. bacteriochlorins A of similar limited strategyaqueous was usedsolubility to solubilize bearingmeso one-aryl amine porphyrins side chain in by organic reductive solvents amination [67 of,68 a]. β-formylated bacteriochlorin (see Otheralso Scheme ammonium-based 5) [66]. A representative water-soluble example derivatives is bacteriochlorin were also24, which prepared possesses by thean ammonium- Lindsey group terminated dialkyl chain, a so-called swallowtail functionality. This moiety was designed to project by introduction of spiro-linked piperidine moieties at the β-positions of a bacteriochlorin [69]. solubilizing groups above and below the plane of the macrocycle, leading to facial encumbrance that The integral spiropiperidine functional groups were quarternized using standard conditions to furnish inhibits macrocycle stacking and increases hydrophilicity. A similar strategy was used to solubilize water-solublemeso-aryl porphyrins derivatives, insuch organic as bacteriochlorinsolvents [67,68]. 25 (Figure1).

Figure 1. Molecular structures of ammonium-substituted bacteriochlorins 24 and 25.

Figure 1. Molecular structures of ammonium-substituted bacteriochlorins 24 and 25. Figure 1. Molecular structures of ammonium-substituted bacteriochlorins 24 and 25.

Molecules 2017, 22, 980 7 of 46

MoleculesOther 2017 ammonium-based, 22, 980 water-soluble derivatives were also prepared by the Lindsey group7 of by 46 Molecules 2017, 22, 980 7 of 47 introduction of spiro-linked piperidine moieties at the β-positions of a bacteriochlorin [69]. The integral Other ammonium-based water-soluble derivatives were also prepared by the Lindsey group by spiropiperidine functional groups were quarternized using standard conditions to furnish water- introduction of spiro-linked piperidine moieties at the β-positions of a bacteriochlorin [69]. The integral soluble derivatives, such as bacteriochlorin 25 (Figure 1). Thespiropiperidine direct introduction functional of groups ammonium were quarternized groups using using a nucleophilic standard conditions Senge arylation to furnish strategy water- was The direct introduction of ammonium groups using a nucleophilic Senge arylation strategy was performedsoluble byderivatives, Anderson such and as bacteriochlorin co-workers on 25 1,15(Figure diaryl 1). porphyrin 26Zn (Scheme7)[ 70]. Porphyrin performed by Anderson and co-workers on 1,15 diaryl porphyrin 26Zn (Scheme 7) [70]. Porphyrin 26 was 26 was functionalizedThe direct introduction at the meso of ammonium-position with groups a Boc-protected using a nucleophilic amino-phenyl Senge arylation group. strategy The resultingwas functionalized at the meso-position with a Boc-protected amino-phenyl group. The resulting performed by Anderson and co-workers on 1,15 diaryl porphyrin 26Zn (Scheme 7) [70]. Porphyrin 26 was derivativederivative27 was 27 was carried carried through through multiple multiple stepssteps to afford afford porphyrin porphyrin dimer dimer 28 that28 that was wasrendered rendered functionalized at the meso-position with a Boc-protected amino-phenyl group. The resulting water-solublewater-soluble by quarternizationby quarternization of of the the amine amine functionalityfunctionality with with CH CH3I.3 I. derivative 27 was carried through multiple steps to afford porphyrin dimer 28 that was rendered water-soluble by quarternization of the amine functionality with CH3I. Li N(TMS)2, Ar Ar Ar Ar 1.THF, 0 °C Lithen H2O N(TMS)2, 2. DDQ N Ar N N Ar N N Ar N N Ar N 1.THF,3. Boc2 0O, °C THF Zn Zn Zn Zn then H2O BocHN H2N NH2 N N 2. DDQ N N N N N N N N N N N N N N 3. Boc2O, THF Zn Zn Zn Zn BocHN H2N NH2 N Ar N 26Zn N Ar N 27 N Ar N N Ar N 28

Ar 26Zn Ar 27 Ar CH3I, DIPEA, ArDMF 28 – O(CH2CH2O)3CH3 2 AcO Ar Ar Ar = CH3I, DIPEA, DMF – O(CH2CH2O)3CH3 2 AcO N Ar N N Ar N Ar = H3C CH3 Zn Zn H3C N N CH3 H3C N N N N CH3 N N N N H3C CH3 Zn Zn H3C N N CH3 29 CH H3C N Ar N N Ar N 3

Scheme 7. meso-Aryl-ammonium bis-acetylene linked porphyrin dimers prepared via Senge arylation,29 as Scheme 7. meso-Aryl-ammonium bis-acetylene linked porphyrinAr dimers prepared viaAr Senge arylation, described by the Anderson group [70]. DIPEA = N,N-diisopropylethylamine. as describedScheme 7. by meso the-Aryl-ammonium Anderson group bis-acetylene [70]. DIPEA linked = Nporphyrin,N-diisopropylethylamine. dimers prepared via Senge arylation, as 2.2. Porphyrinsdescribed by Carrying the Anderson Pyridyl/Pyridinium group [70]. DIPEA Groups = N ,N-diisopropylethylamine. 2.2. Porphyrins Carrying Pyridyl/Pyridinium Groups 2.2. Porphyrins Carrying Pyridyl/Pyridinium Groups 2.2.1. meso-Tetrakispyridiniumporphyrins 2.2.1. meso-Tetrakispyridiniumporphyrins 2.2.1.meso meso-Tetrapyridylporphyrins-Tetrakispyridiniumporphyrins and the corresponding meso-tetrakis(methylpyridinium)porphyrins mesoare long-Tetrapyridylporphyrins known, and their intercalation and the into corresponding DNA was studiedmeso in-tetrakis(methylpyridinium)-porphyrins detail [55,56]. Pyridinium porphyrins meso-Tetrapyridylporphyrins and the corresponding meso-tetrakis(methylpyridinium)porphyrins continue to attract attention as next generation photosensitizers for PDT. Various new mesoare longare long known, known, and and their intercalation intercalation into intoDNA DNAwas studied was studiedin detail [55,56]. in detail Pyridinium [55,56]. porphyrins Pyridinium tetrakispyridiniumporphyrin derivatives were prepared using a range of electrophiles to quarternize porphyrinscontinue continue to attract to attention attract attention as next genera as nexttion generation photosensitizers photosensitizers for PDT. Various for PDT. new Various meso- new the pyridine nitrogens (Scheme 8). meso-tetrakispyridiniumporphyrintetrakispyridiniumporphyrin derivatives derivatives were prepared were prepared using a range using of electrophiles a range of to electrophilesquarternize to quarternizethe pyridine the pyridine nitrogensnitrogens (Scheme 8). (Scheme 8). 4 X– Quarternization R N N Conditions 4 X– ClCH2CH2OH, DMF R QuarternizationPhCH Cl, DMF Conditions2 N N 4-OMe-PhCH2Cl, DMF ClCH2CH2OH, DMF 3,4,5-OMe-PhCH2Cl, DMF PhCH2Cl, DMF BrCH2CHCH2, DMF 4-OMe-PhCH2Cl, DMF N N N N ClCH2CHCH2, DMF 3,4,5-OMe-PhCH Cl, DMF H N R H N 2 R N N BrCH CHCH , DMF H H 2 2 N N N N N N N N ClCH2CHCH2, DMF H H N R N R N H N H N N – – N N 31a: R = CH2CH2OH, X = NO3 – – 30 31b: R = CH2Ph, X = Cl 31c: R = CH -4-OMePh, X– = Cl– N 2 – – N 31a: R = CH2CH2OH, X = NO3– – 31d: R = CH2-3,4-5-OMePh,– – X = Cl 30 R 31b: R = CH2Ph, X = Cl – – 31e: R = CH2CH=CH2, X =– Br – 31c: R = CH2-4-OMePh,– X = –Cl N 31f: R = CH2CH=CH2 X = Cl – – N 31d: R = CH2-3,4-5-OMePh, X = Cl R – – 31e: R = CH2CH=CH2, X = Br – – Scheme 8. Quarternization options of meso-tetrakis(4-pyridyl)porphyrin.31f: R = CH2CH=CH 2 X = Cl

Orlandi andScheme Schemeco-workers 8. Quarternization8. Quarternization prepared meso optionsoptions-tetrakis(4-pyridinium)porphyrins of mesomeso-tetrakis(4-pyridyl)porphyrin.-tetrakis(4-pyridyl)porphyrin. (31) by reaction of meso- tetra(4-pyridyl)porphyrin (30) with various benzyl chlorides to study the effect of polar alkylating groups Orlandi and co-workers prepared meso-tetrakis(4-pyridinium)porphyrins (31) by reaction of meso- on their antibacterial activity [71]. The benzylation conditions required were more vigorous (reflux in Orlanditetra(4-pyridyl)porphyrin and co-workers (30) prepared with variousmeso benzyl-tetrakis(4-pyridinium)porphyrins chlorides to study the effect of polar alkylating (31) by groups reaction of meso-tetra(4-pyridyl)porphyrinon their antibacterial activity [71]. (30) The with benzylation various benzyl conditions chlorides required to study were themore effect vigorous of polar (reflux alkylating in groups on their antibacterial activity [71]. The benzylation conditions required were more vigorous (reﬂux in DMF for 24 h) than typical for pyridine alkylations using alkyl halides. The water-soluble products were recovered by precipitation with Et2O and ﬁltration. Similarly, Ghazaryan and co-workers prepared a variety of meso-substituted N-substituted tetrapyridiniumporphyrins with different central metals (Ag, Zn, Co and Fe) and alkylating agents (allyl-, oxyethyl-, butyl- and Molecules 2017, 22, 980 8 of 46

DMF for 24 h) than typical for pyridine alkylations using alkyl halides. The water-soluble products Molecules 2017, 22, 980 8 of 47 were recovered by precipitation with Et2O and filtration. Similarly, Ghazaryan and co-workers prepared a variety of meso-substituted N-substituted tetrapyridiniumporphyrins with different central metals (Ag, methallyl-substitutedZn, Co and Fe) and alkylating derivatives) agents [72 (allyl-,]. A PEGylated oxyethyl-, butyl- derivative and methallyl-substituted of meso-tetrakispyridiniumporphyrin derivatives) [72]. A PEGylated derivative of meso-tetrakispyridiniumporphyrin was also prepared by alkylation of was also prepared by alkylation of meso-tetra(4-pyridyl)-porphyrin with a short PEG-bromide [73,74]. meso-tetra(4-pyridyl)-porphyrin with a short PEG-bromide [73,74]. m p meso FluorinatedFluorinated derivatives derivatives of of m-- or or p-linked-linked meso-pyridyl-pyridyl porphyrins porphyrins were were prepared prepared along along Adler Adler + − synthesissynthesis routes routes [75 ].[75].N -AlkylationN-Alkylation of of the the pyridylpyridyl substituentssubstituents by by treatment treatment with with (CH (CH3)3O3)+BF3O4− BF4 affordedafforded the the tetra-alkylated tetra-alkylated products products 32 andand 3333, respectively,, respectively, as their as their tetrafluoroborate tetraﬂuoroborate salts (Figure salts 2). (Figure 2).

– – CH3 4 BF4 4 BF4 N H C 3 N

Y X F

X Y F CH3 N N N N N H N CH H H3C N H 3 H N N N N N Y X H3C F

X Y F 33 32a: X = H, Y = H N N 32b: X = H, Y = F CH 32c: X = F, Y = F 3 CH3 FigureFigure 2. Molecular 2. Molecular structures structuresof of mesomeso-pyridinium-substituted porphyrins porphyrins 32 and32 and33. 33.

In search of dual-action photo- and cytotoxic anti-cancer agents, various metal complexes were coordinatedIn search of to dual-actionthe outer pyridyl photo- nitrogens and cytotoxic in tetrapyridylporphyrins anti-cancer agents, (Scheme various 9). metal Ruthenium, complexes wererhodium coordinated and iridium to the outercomplexes pyridyl were nitrogens thus prepared in tetrapyridylporphyrins by Therrien and co-workers (Scheme [76] by9 ).treatment Ruthenium, rhodiumof meso and-tetrapyridylporphyrin iridium complexes 30 were with thus various prepared metal arene by Therrien salts to afford and co-workers the water-soluble [76] by organic treatment of mesometallic-tetrapyridylporphyrin complexes of type 34. They30 with also prepared various mixed metal arene-ru arenethenium salts to substituted affordthe porphyrins water-soluble in organica similar metallic manner, complexes producing of type mono-34 .and They tetrametal also preparedlated derivatives mixed arene-rutheniumof 3- and 4-tetrapyridyl- substituted porphyrinsporphyrins in [77]. a similar Both cis manner,- and trans producing-platin conjugates mono- of andporphyrins tetrametallated were prepared derivatives by treatment of of 3- and 30 with cis- or trans-Pt(II) complexes, respectively [77]. The gallium complexes of these compounds 4-tetrapyridyl-porphyrins [77]. Both cis- and trans-platin conjugates of porphyrins were prepared (such as 35) were prepared by Odani and co-workers [78] and also tested as photosensitizers for by treatmentcancer therapy. of 30 Inwith addition,cis- or tetrapyridylporphyrinstrans-Pt(II) complexes, with respectivelyruthenium nitrosyl [77]. groups The gallium substituted complexes at of thesetheircompounds periphery were (such reported as 35 by) were the group prepared of Alessio, by Odani generated and by co-workers reaction of [3078 ]with and ruthenium also tested as photosensitizersnitrosyls and purified for cancer by co therapy.lumn chromatography In addition, (CHCl tetrapyridylporphyrins3/5% EtOH as eluent) with[79]. ruthenium nitrosyl groups substituted at their periphery were reported by the group of Alessio, generated by reaction of 2.2.2. A3B and Other meso-Pyridiniumporphyrins 30 with ruthenium nitrosyls and purified by column chromatography (CHCl3/5% EtOH as eluent) [79]. A number of symmetrically substituted pyridylporphyrins have been prepared in the search for 2.2.2.the A3 nextB and generation Other meso of -Pyridiniumporphyrinsanticancer PDT agents. However, to further optimize their tumor-targeting andA number biodistribution of symmetrically properties, the substituted porphyrin pyridylporphyrins needs to be amenable have to further been modifications prepared inthe that search will for the nextallow, generation for example, of anticancerthe conjugation PDT of agents. the porphy However,rin to a to targeting further molecule. optimize Thus, their tumor-targetinga variety of examples emerged that use A3B porphyrins bearing three meso-pyridinium groups as the water- and biodistribution properties, the porphyrin needs to be amenable to further modifications that soluble framework of the chromophore, with the fourth meso-aryl ring available for further will allow, for example, the conjugation of the porphyrin to a targeting molecule. Thus, a variety manipulations (Scheme 10). The parent A3B porphyrins are typically synthesized as statistical mixtures by of examplesAdler condensation emerged thatof pyridylaldehyde, use A3B porphyrins the desired bearing arylaldehydes, three meso and-pyridinium pyrrole, followed groups by as the water-solublechromatographic framework separation of the of the chromophore, product mixture. with The the A3B fourth porphyrinmeso precursors-aryl ring are available functionalized for further manipulationsat the remaining (Scheme meso 10-aryl). The group parent and A 3NB-alkylated porphyrins with are CH typically3I, with synthesizedthe order of asthese statistical operations mixtures by Adlerdepending condensation on the functionality of pyridylaldehyde, present (see below). the desired arylaldehydes, and pyrrole, followed by chromatographicUsing this separation strategy, a of pyrene-substituted the product mixture. trispyridyl The A 3AB3 porphyrinB porphyrin precursors could be prepared are functionalized [80] (Scheme 10). Its N-alkylation with methyl p-toluenesulfonate in refluxing CHCl3/CH3NO2 afforded at the remaining meso-aryl group and N-alkylated with CH3I, with the order of these operations dependingthe tris- onN-methyl the functionality pyridiniumporphyrin present (see37b. below).The group of Boyle synthesized tripyridyl A3B porphyrin 37a with the fourth aryl ring bearing a bioconjugatable isocyanate group. Using this strategy, a pyrene-substituted trispyridyl A3B porphyrin could be prepared [80] (Scheme 10). Its N-alkylation with methyl p-toluenesulfonate in refluxing CHCl3/CH3NO2 afforded the tris-N-methyl pyridiniumporphyrin 37b. The group of Boyle synthesized tripyridyl A3B porphyrin 37a with the fourth aryl ring bearing a bioconjugatable isocyanate group. Molecules 2017, 22, 980 9 of 47 Molecules 2017, 22, 980 9 of 46

SchemeScheme 9. M-Arene9. M-Arene complexes complexesof ofmeso meso-tetra(4-pyridyl)porphyrin,-tetra(4-pyridyl)porphyrin, as asdescribed described by the by groups the groups of of Therrien [76,77], and Odani [78]. Therrien [76,77], and Odani [78].

The N-alkylation step (standard CH3I alkylation conditions) needed to be performed after the formationThe N-alkylation of the isocyanate step (standard group to CH avoid3I alkylation unwanted conditions) N-alkylation needed of the amine to be performedprecursors [81]. after the formationA number of the of isocyanatep-substituted group phenyl to derivatives avoid unwanted allowed Na -alkylationwide range ofof thefunctionalizations. amine precursors For [81]. A numberinstance, of pSong-substituted et al. synthesized phenyl derivativesA3B pyridyl porphyrin allowed a 37j wide with range the fourth of functionalizations. aryl group bearing For a Pt(II) instance, complex linked to the hydroxyl group of the meso-phenol group by a triethylene glycol linker [82]. Song et al. synthesized A3B pyridyl porphyrin 37j with the fourth aryl group bearing a Pt(II) N-Alkylation of the three pyridyl groups, followed by Boc-deprotection and complexation with the complex linked to the hydroxyl group of the meso-phenol group by a triethylene glycol linker [82]. Pt(II) precursor, yielded the A3B platinum-porphyrin conjugate 37j. A similar approach was taken by N-Alkylation of the three pyridyl groups, followed by Boc-deprotection and complexation with the group of Alessio to synthesize water-soluble 99mTc(I)/Re(I)-porphyrin conjugates, such as 37l, the Pt(II)utilizing precursor, an amide-linked yielded spacer the A between3B platinum-porphyrin the aryl group and the conjugate 99mTc(I)/Re(I)37j. ion A similar[83,84]. The approach water- was 99m takensoluble by the derivatives group of were Alessio purified to synthesize by normal water-solublephase silica gel columnTc(I)/Re(I)-porphyrin chromatography (CH conjugates,2Cl2/MeOH such 99m as 37lmixtures)., utilizing These an amide-linkedtypes of compounds spacer can between also be co thenjugated aryl group to cancer-targeting and the Tc(I)/Re(I)peptides for use ion in [83 ,84]. The water-solublecancer therapy [85]. derivatives Cu(II)-based were acylhydrazone purified by porphyrin-derivatives normal phase silica 37m geland column37n could chromatography be obtained (CH2usingCl2/MeOH a similar mixtures). strategy [86]. These The group types of of Boyle compounds synthesized can an also A3B beporphyrin conjugated that could to cancer-targeting be further peptidesfunctionalized for use in to cancer establish therapy an azide [85 group]. Cu(II)-based [87]. The azide acylhydrazone functionality porphyrin-derivatives was used in a click reaction37m and to introduce an 18F-terminated short PEG chain to generate water-soluble porphyrin 37k for PDT/PET 37n could be obtained using a similar strategy [86]. The group of Boyle synthesized an A3B porphyrin theranostic applications [87]. After N-methylation of the pyridyl nitrogens, the subsequent synthetic that could be further functionalized to establish an azide group [87]. The azide functionality was steps required precipitation of the product using Et2O/MeOH mixtures. The final products were used in a click reaction to introduce an 18F-terminated short PEG chain to generate water-soluble purified by passing through a column of neutral alumina. porphyrin 37k for PDT/PET theranostic applications [87]. After N-methylation of the pyridyl nitrogens, Gasparyan and co-workers synthesized an A3B amphiphilic trispyridylporphyrin with one meso-aryl the subsequentgroup carrying synthetic a long alkyl steps chain required using a precipitation mixed aldehyde of Adler the product condensation using [88]. Et2 O/MeOHQuarternization mixtures. The finalof the products pyridyl were groups purified with by3-bromopropene passing through provided a column th ofe neutralwater-soluble alumina. vinyl-substituted trispyridiniumporphyrinsGasparyan and co-workers 38 and synthesized 38Ag (Figure an3) that A3B were amphiphilic isolated by trispyridylporphyrinprecipitation with acetone. with one meso-aryl group carrying a long alkyl chain using a mixed aldehyde Adler condensation [88]. Quarternization of the pyridyl groups with 3-bromopropene provided the water-soluble vinyl-substituted trispyridiniumporphyrins 38 and 38Ag (Figure3) that were isolated by precipitation with acetone.

Molecules 2017, 22, 980 10 of 47 Molecules 2017, 22, 980 10 of 46 Molecules 2017, 22, 980 10 of 46

Scheme 10. A3B tri-pyridyl porphyrins prepared by Adler synthesis and subsequent synthetic Scheme 10. A3B tri-pyridyl porphyrins prepared by Adler synthesis and subsequent synthetic Schememodification. 10. A dmpda3B tri-pyridyl = N,N′ -dimethyl-1,3-propanediamine,porphyrins prepared by Adler dach synthesis = 1,2-diaminocyclohexane. and subsequent synthetic modiﬁcation. dmpda = N,N0-dimethyl-1,3-propanediamine, dach = 1,2-diaminocyclohexane. modification. dmpda = N,N′-dimethyl-1,3-propanediamine, dach = 1,2-diaminocyclohexane.

Figure 3. Molecular structure of meso-pyridinium-substituted porphyrin 38/38Ag. Figure 3. Molecular structure of meso-pyridinium-substituted porphyrin 38/38Ag. Figure 3. Molecular structure of meso-pyridinium-substituted porphyrin 38/38Ag. Yasuda and co-workers prepared AB3 phosphorus porphyrin 39 [89]. Its axial chloro-ligands couldYasuda be exchanged and co-workers for simple prepared alcohols AB 3and phosphorus oligoethylene porphyrin glycol 39chains [89]. toIts generateaxial chloro-ligands hydrophilic Yasudacouldphosphorus be andexchanged porphyrins co-workers for 40 simple and prepared 41 . Nalcohols-Alkylation AB 3andphosphorus ofoligoe the mesothylene-pyridyl porphyrin glycol group chains39 in 40a[89 to–].40d generate Its or axial 41 then hydrophilic chloro-ligands furnished couldphosphoruswater-soluble be exchanged porphyrins derivatives, for simple40 andwith 41 alcoholssolubility. N-Alkylation in and water of oligoethylene the of meso around-pyridyl ~10 glycol groupmM for in chains compounds40a–40d to or generate 41 42a then–42d furnished hydrophilicand 43. phosphoruswater-soluble(Scheme porphyrins11) [89]. derivatives, An equivalent40 andwith 41solubilitymethodology. N-Alkylation in water was usedof of around theto intrmeso ~10oduce -pyridylmM axial for PEG compounds group chains in [90]. 40a42a ––42d40d andor 4341. then furnished(SchemeUsing water-soluble 11) a[89]. fundamentally An equivalent derivatives, different methodology with strategy solubility was toward used to meso in intr water-pyridyloduce ofaxial porphyrins, around PEG chains ~10 pyridyl [90]. mM forsubstituents compounds 42a–42dcan beandUsing introduced43 a. fundamentally (Scheme to meso 11-brominated)[ different89]. An strategy porphyrins equivalent toward by methodology using meso-pyridyl Suzuki couplings. porphyrins, was used For topyridyl instance, introduce substituents the group axial PEG canof Lindsey be introduced reported to mesothe -brominatedsynthesis of porphyrinsa series of amphiphilic by using Suzuki hydroporphyrins couplings. For prepared instance, bythe Suzukigroup chains [90]. ofcoupling Lindsey of reported a pyridyl the boronic synthesis ester of witha series meso of-bromo-chlorins amphiphilic hydroporphyrins or bacteriochlorins prepared [34]. Key by Suzukichlorin meso Usingcoupling a fundamentallyof a pyridyl boronic different ester strategywith meso toward-bromo-chlorins-pyridyl or bacterio porphyrins,chlorins [34]. pyridyl Key substituentschlorin can be introduced to meso-brominated porphyrins by using Suzuki couplings. For instance, the group of Lindsey reported the synthesis of a series of amphiphilic hydroporphyrins prepared by Suzuki coupling of a pyridyl boronic ester with meso-bromo-chlorins or bacteriochlorins [34]. Key chlorin building Molecules 2017, 22, 980 11 of 47

Molecules 2017, 22, 980 11 of 46 blockMolecules45 was 2017 prepared, 22, 980 by regioselective meso-bromination of chlorin 44 using NBS (Scheme11 of 12 46)[ 91]. In thebuilding ﬁnal stepblock of45 thewas synthesis,prepared bythe regioselective pyridyl functional meso-bromination group of was chlorin quarternized 44 using NBS with (Scheme CH I to building block 45 was prepared by regioselective meso-bromination of chlorin 44 using NBS (Scheme 3 furnish12) bacteriochlorin[91]. In the final step46. of This the strategysynthesis, is the ﬂexible pyridyl and functional tolerant group of a was number quarternized of other with substituents CH3I 12)to furnish [91]. In bacteriochlorinthe final step of 46 the. This synthesis, strategy the is flexiblepyridyl andfunctional tolerant group of a numberwas quarternized of other substituents with CH3I on the hydroporphyrin framework. Thus, chlorin 47 and bacteriochlorin 48 were prepared along toon furnish the hydroporphyrin bacteriochlorin framework. 46. This strategy Thus, ischlorin flexible 47 and and tolerant bacteriochlorin of a number 48 wereof other prepared substituents along analogous routes. onanalogous the hydroporphyrin routes. framework. Thus, chlorin 47 and bacteriochlorin 48 were prepared along analogous routes.

Scheme 11. Water-soluble AB3 phosphorus porphyrins, as described by the group of Yasuda [89]. Scheme 11. Water-soluble AB phosphorus porphyrins, as described by the group of Yasuda [89]. Scheme 11. Water-soluble AB3 3 phosphorus porphyrins, as described by the group of Yasuda [89].

Scheme 12. Amphiphilic meso-pryridyl chlorins and bacteriochlorins, as described by the group of Scheme 12. Amphiphilic meso-pryridyl chlorins and bacteriochlorins, as described by the group of SchemeLindsey 12. Amphiphilic[91]. meso-pryridyl chlorins and bacteriochlorins, as described by the group of Lindsey [91]. Lindsey [91]. In an analogous manner, Anderson and co-workers employed a Suzuki coupling strategy to introduceIn an pyridylanalogous functional manner, groups Anderson to meso and-dibrominated co-workers employed bis-acetylen a eSuzuki linked coupling porphyrin strategy dimer 49to Inintroduce(Scheme an analogous 13) pyridyl [70]. Afterfunctional manner, coupling Andersongroups with to 4-pyridinylboronic meso and-dibrominated co-workers acid, bis-acetylen employed both mesoe a linked-pyridyl Suzuki porphyrin functional coupling dimer groups strategy 49 to introduce(Schemein 50 were pyridyl 13) methylated [70]. functional After under coupling groups standard with to conditions4-pyridinylboronicmeso-dibrominated to afford theacid, bis-acetylenedicationic both meso product-pyridyl linked 51. functionalThis porphyrin water-soluble groups dimer 49 in 50 were methylated under standard conditions to afford the dicationic product 51. This water-soluble (Schemeporphyrin 13)[70 dimer]. After was coupling purified withby precipitation 4-pyridinylboronic from DMF/Et acid,2O. both meso-pyridyl functional groups in porphyrin dimer was purified by precipitation from DMF/Et2O. 50 were methylated under standard conditions to afford the dicationic product 51. This water-soluble porphyrin dimer was puriﬁed by precipitation from DMF/Et2O. Molecules 2017, 22, 980 12 of 47 Molecules 2017, 22, 980 12 of 46

HO OH Ar Ar B Ar Ar Molecules 2017, 22, 980 12 of 46 N N N N N N N N N , Br Zn Zn Br N Zn Zn N N Pd(PPhHO3)2Cl2OH, NaHCO3, N N Ar N Ar N B N Ar N Ar N THF, DMF, H2O

N Ar N 49 N Ar N N Ar N N Ar N 50 N , Br Zn Zn Br N Zn Zn N CH3I, DMF Pd(PPh3)2Cl2, NaHCO3, N N N N N Ar N N Ar N · 2 I THF, DMF, H2O O(CH2CH2O)3CH3 Ar Ar Ar 49 N Ar N N N 50 Ar = Zn Zn N CH H3C N CH3I, DMF 3 N Ar N N Ar N · 2 I

O(CH2CH2O)3CH3 N Ar N N Ar N 51 Ar = Zn Zn H3C N N CH3 Scheme 13. Preparation of a meso-pyridinium-functionalized Nbis-acetyleneN linked porphyrinN N dimer, Scheme 13. Preparation of a meso-pyridinium-functionalized bis-acetylene linked porphyrin dimer, as as described by the group of Anderson [70]. described by the group of Anderson [70]. Ar Ar 51 SchemeAnderson 13. andPreparation coworkers of a alsomeso -pyridinium-functionalizedintroduced pyridyl substituents bis-acetylene to the linked meso -positionporphyrin ofdimer, trans -AB Andersonporphyrinsas described by and Sonoga by coworkersthe groupshira ofcoupling Anderson also introducedof [70]. meso -alkynyl pyridyl porphyrin substituents with 4-iodopyridine. to the meso The-position pyridyl of trans-ABgroups porphyrins were then quarterniz by Sonogashiraed with the coupling electrophiles of meso CH3-alkynylI, 1,4-butane porphyrin sultone or with5-iodo- 4-iodopyridine.N,N,N-tri- methylpentan-1-ammoniumAnderson and coworkers [92–94]. also introd uced pyridyl substituents to the meso-position of trans-AB The pyridyl groups were then quarternized with the electrophiles CH3I, 1,4-butane sultone or porphyrins by Sonogashira coupling of meso-alkynyl porphyrin with 4-iodopyridine. The pyridyl 5-iodo-N,N,N-tri-methylpentan-1-ammonium [92–94]. groups2.2.3. Other were Pyridyl-Substituted then quarternized withPorphyrins the electrophiles CH3I, 1,4-butane sultone or 5-iodo-N,N,N-tri- methylpentan-1-ammonium [92–94]. 2.2.3. OtherPorphyrins Pyridyl-Substituted bearing alkylated Porphyrins pyridinium substituents in positions not directly linked to the meso- or β-positions of the macrocycle were also prepared. For example, Marzilli and co-workers 2.2.3. Other Pyridyl-Substituted Porphyrins Porphyrinssynthesized porphyrins bearing alkylated 52 (Figure pyridinium 4) with the pyridyl substituents groups link in positionsed through not sulfonamide directly linkedlinkages to to the the meso- or β-positionsp-phenylPorphyrins positions of the macrocyclebearing of meso alkylated-tetraarylporphyrins were alsopyridinium prepared. [59,95]. substitu For They example,ents inve in positionsstigated Marzilli whether not and directly co-workers distant linked pyridinium synthesized to the porphyrinsmesogroups- or 52are β (Figure-positionsequally 4competent) withof the the macrocycle in pyridyl mediating groupswere DNA-intercalation. also linked prep throughared. DipicolylamineFor sulfonamideexample, Marzilli (DPA) linkages substituents and toco-workers the couldp-phenyl positionssynthesizedalso be of linkedmeso porphyrins-tetraarylporphyrins through the 52 sulfonamide(Figure 4) with [59 group ,the95]. pyridyl (53 They), to groupsprepare investigated link rhenium-baseded through whether sulfonamide radiopharmaceuticals distant pyridinium linkages to [96]. the groups are equallyp-phenyl competent positions of in meso mediating-tetraarylporphyrins DNA-intercalation. [59,95]. They Dipicolylamine investigated whether (DPA) substituentsdistant pyridinium could also be linkedgroups through are equally the competent sulfonamide in mediating group ( DNA-intercalation.53), to prepare rhenium-based Dipicolylamine radiopharmaceuticals(DPA) substituents could [96]. also be linked through the sulfonamide group (53), to prepare rhenium-based radiopharmaceuticals [96].

Figure 4. Molecular structures of sulfonamide-linked pyridinium/dipicolylamine-substituted porphyrins 52 and 53.

A remarkable octapyridiniumporphyrin 55 was prepared by Prato and co-workers [97] by FigureFigure 4. 4.Molecular Molecular structures structures of sulfonamide-linked of sulfonamide-linked pyridinium/dipicolylamine-substituted pyridinium/dipicolylamine-substituted porphyrins treatment52 and of 53 meso. -tetrakis(2,6-bis-(bromomethyl)-4-t-butylphenyl) porphyrin 54 with t-butylpyridine porphyrins 52 and 53. (Scheme 14). The octapyridyl porphyrin 55 was purified by crystallization from Et2O/MeOH. The octacationicA remarkable compound octapyridiniumporphyrin 55 was used in studies toward55 was assembliesprepared byfor Pratolight-harvesting and co-workers applications. [97] by Atreatment remarkable of meso octapyridiniumporphyrin-tetrakis(2,6-bis-(bromomethyl)-4-55 wast-butylphenyl) prepared porphyrin by Prato 54 and with co-workers t-butylpyridine [97 ] by treatment(Scheme of meso14). -tetrakis(2,6-bis-(bromomethyl)-4-The octapyridyl porphyrin 55 was purifiedt-butylphenyl) by crystallization porphyrin from54 Etwith2O/MeOH.t-butylpyridine The octacationic compound 55 was used in studies toward assemblies for light-harvesting applications. (Scheme 14). The octapyridyl porphyrin 55 was puriﬁed by crystallization from Et2O/MeOH. The octacationic compound 55 was used in studies toward assemblies for light-harvesting applications.

Molecules 2017, 22, 980 13 of 47 Molecules 2017, 22, 980 13 of 46

Molecules 2017, 22, 980 13 of 46

Scheme 14. An octapyridiniumporphyrin, as described by the group of Prato [97]. Scheme 14. An octapyridiniumporphyrin, as described by the group of Prato [97 ]. The introductionScheme 14. of An pyridinium octapyridiniumporphyrin, groups can also as debescribed achieved by the by group esterification of Prato [97]. of a β-alkylester Thewith introductiona suitable pyridine-derivatized of pyridinium groupsalcohol. Thus, can also cationic be achieved water-soluble by esteriﬁcation ester 56 was prepared of a β-alkylester from The introduction of pyridinium groups can also be achieved by esterification of a β-alkylester withchlorin a suitable e6 ( pyridine-derivatized11) by esterification with alcohol. 2-(2-hydroxyethyl) Thus, cationicpyridine, water-soluble followed esterby quarternization56 was prepared with from with a suitable pyridine-derivatized alcohol. Thus, cationic water-soluble ester 56 was prepared from CH3I (cf. Scheme 4) [62]. Derivatives 56 (Figure 5) and related 13 possess sharp absorbance spectra in chlorinchlorin e6 ( 11e6) ( by11) esteriﬁcationby esterification with with 2-(2-hydroxyethyl)pyridine, 2-(2-hydroxyethyl)pyridine, followed followed by byquarternization quarternization with with Tris-HCl buffer at pH 7.6, indicating little aggregation of the chromophores. CH3ICH (cf.3I Scheme(cf. Scheme4)[ 4)62 [62].]. Derivatives Derivatives56 56 (Figure(Figure 55)) and related related 1313 possesspossess sharp sharp absorbance absorbance spectra spectra in in Tris-HClTris-HCl buffer buffer at pH at pH 7.6, 7.6, indicating indicating little little aggregation aggregation of the the chromophores. chromophores.

Figure 5. Molecular structures of pyridinium-substituted chlorin 56 and phosphorus porphyrin 57.

FigurePyridiniumFigure 5. Molecular 5. Molecular substituents structures structures have of of pyridinium-substituted pyridinium-substitutedalso been introduced chlorin in chlorin the 56 axia56 andandl positionsphosphorus phosphorus of porphyrin phosphorus porphyrin 57. and57. antimony meso-tetraphenyl porphyrins by axial exchange using a pyridine-derivatized alcohol (cf. to Pyridinium substituents have also been introduced in the axial positions of phosphorus and Scheme 11) [89,98]. Alkylation of the axial pyridyl moiety with a range of alkyl bromides furnished antimonyPyridinium meso substituents-tetraphenyl porphyrins have also by been axial introduced exchange us ining the a pyridine-derivatized axial positions of alcohol phosphorus (cf. to and derivatives such as 57 (Figure 5), with a water-solubility of ~3 mM [89]. antimonySchememeso 11)-tetraphenyl [89,98]. Alkylation porphyrins of the axial by axial pyridyl exchange moiety usingwith a arange pyridine-derivatized of alkyl bromides furnished alcohol (cf. to Schemederivatives2.2.4. 11 meso)[89-Imidazolium ,such98]. Alkylationas 57 (Figure Porphyrins of 5), the with axial a water-solubility pyridyl moiety of ~3 with mM a [89]. range of alkyl bromides furnished derivatives such as 57 (Figure5), with a water-solubility of ~3 mM [89]. 2.2.4.The meso synthesis-Imidazolium of porphyrins Porphyrins carrying N-alkylated meso-imidazolyl functionalities represents another strategy for the preparation of cationic porphyrins [99]. Lindsey and co-workers prepared porphyrins 2.2.4. mesoThe-Imidazolium synthesis of porphyrins Porphyrins carrying N-alkylated meso-imidazolyl functionalities represents another with one or two meso-imidazolyl groups by starting from imidazole-functionalized dipyrromethane strategy for the preparation of cationic porphyrins [99]. Lindsey and co-workers prepared porphyrins Theprecursors synthesis [100,101]. of porphyrinsMono-imidazolyl carrying porphyrinN-alkylated 58 was alkylatedmeso-imidazolyl with various functionalitiesalkylating reagents. represents The with one or two meso-imidazolyl groups by starting from imidazole-functionalized dipyrromethane anotherresulting strategy imidazolium for the porphyrins preparation were of studied cationic for porphyrins their use in photodynamic [99]. Lindsey therapy. and co-workers The zwitterionic prepared precursors [100,101]. Mono-imidazolyl porphyrin 58 was alkylated with various alkylating reagents. The imidazolium sulfonate porphyrin 60Zn, for example, is the product obtained when 1,4-butane porphyrinsresulting withimidazolium one or porphyrins two meso were-imidazolyl studied for groups their use by in photodynamic starting from therapy. imidazole-functionalized The zwitterionic sultone was used as the alkylating reagent (Scheme 15) [100]. dipyrromethaneimidazolium precursorssulfonate porphyrin [100,101 ].60Zn Mono-imidazolyl, for example, is porphyrinthe product58 obtainedwas alkylated when 1,4-butane with various alkylatingsultone reagents. was used The as the resulting alkylati imidazoliumng reagent (Scheme porphyrins 15) [100]. were studied for their use in photodynamic therapy. The zwitterionic imidazolium sulfonate porphyrin 60Zn, for example, is the product obtained when 1,4-butane sultone was used as the alkylating reagent (Scheme 15)[100].

Molecules 2017, 22, 980 14 of 47 Molecules 2017, 22, 980 14 of 46

Molecules 2017, 22, 980 14 of 46

SchemeScheme 15. 15. mesomeso-Imidazolium-Imidazolium porphyrins, porphyrins, as described as by described the groups by of Lindsey the groups and Hamblin of Lindsey [100,101]. and Hamblin [100,101]. 3. Water-Soluble Porphyrins Bearing Anionic Substituents Scheme 15. meso-Imidazolium porphyrins, as described by the groups of Lindsey and Hamblin [100,101]. 3. Water-Soluble3.1. Porphyrins Porphyrins with Carboxylate Bearing Functional Anionic Groups Substituents 3. Water-SolubleMany naturally Porphyrins occurring Bearing porphyrins Anionic contain Substituents acetic acid or propionic acid side chains [102]. 3.1. PorphyrinsWith increasing with Carboxylatenumber of acid Functional side chains, Groups their solubility in aqueous solution increases, with the 3.1. Porphyrins with Carboxylate Functional Groups Manyuroporphyrins naturally being occurring freely soluble, porphyrins particularly contain in solutions acetic acid of basic or propionicpH (Scheme acid 16) [102]. side chains [102]. Many naturally occurring porphyrins contain acetic acid or propionic acid side chains [102]. With increasing number of acid side chains, their solubility in aqueous solution increases, with the With increasing number of acid side chains, their solubility in aqueous solution increases, with the uroporphyrinsuroporphyrins being being freely freely soluble, soluble, particularly particularly inin solutionssolutions of of basic basic pH pH (Scheme (Scheme 16) 16 [102].)[102 ].

Scheme 16. Increasing water-solubility of the naturally occurring porphyrins with increasing number of carboxylic acid functionalities.

This suggests that the introduction of carboxylic acid functional groups to the periphery of SchemeScheme 16. Increasing 16. Increasing water-solubility water-solubility of of the the naturallynaturally occurring occurring porphyrins porphyrins with with increasing increasing number number porphyrinsof carboxylic might acid be functionalities. an effective way of furnishing water-soluble derivatives. This is, in fact, also of carboxylic acid functionalities. observed. To simplify the purification of the porphyrins, the carboxylate groups are often masked throughoutThis suggests the synthesis that the as introductionesters and are of re vealedcarboxylic by saponification acid functional in groupsthe final to step. the periphery of Thisporphyrinsmeso suggests-Tetrakis(4-carboxyphenyl)porp might that be thean effective introduction way of of hyrin,furnishing carboxylic and itswater-soluble ester, acid functionalare well derivatives. known, groups andThis to readilyis, the in fact, periphery synthe- also of porphyrinsobserved.sized by might Tocondensation simplify be an effectivethe of purification the waycorresponding of of furnishing the po rphyrins,aldehydes water-soluble the with carboxylate pyrrole derivatives. [103–105].groups are This Theyoften is, aremasked in fact,also also observed.throughoutcommercially To simplify the available synthesis the [58]. purification as esters Carboxylate andof are thegroups revealed porphyrins, may by al saponificationso be the introduced carboxylate in the to thefinal groups porphyrin step. are by often starting masked throughoutwithmeso more the-Tetrakis(4-carboxyphenyl)porp synthesiselaborate building as esters blocks and arecontaining revealedhyrin, and esters. by its saponification ester,Classic are carboxylated well inknown, the finalmeso and-aryl step.readily porphyrins, synthe- mesosizedsuch-Tetrakis(4-carboxyphenyl)porphyrin, asby meso condensation-tetrakis(4-carboxyphenyl)porphyrin, of the corresponding and aldehydes have its ester, been with areprepared wellpyrrole known, by Adler[103–105]. and synthesis readily They with are synthe-sized esteralso commercially available [58]. Carboxylate groups may also be introduced to the porphyrin by starting by condensationsubstituted benzaldehydes of the corresponding followed by aldehydes saponification with of pyrrole the esters [103 [40].–105 Tetracarboxylated]. They are also palladium commercially withporphyrin more 62elaborate was prepared building thusly, blocks whereby containing the carboxylate esters. Classic moieties carboxylated were revealed meso-aryl by standard porphyrins, ester available [58]. Carboxylate groups may also be introduced to the porphyrin by starting with suchsaponification as meso-tetrakis(4-carboxyphenyl)porphyrin, conditions after the palladium insertion have stepbeen (Scheme prepared 17) by [106]. Adler synthesis with ester- moresubstituted elaborateAn introduction benzaldehydes building of esters blocks followed to containingthe βby-positions saponification esters. of a porphyrin of Classic the esters from carboxylated [40]. ester-substituted Tetracarboxylatedmeso building-aryl palladium porphyrins, blocks suchporphyrinis as alsomeso possible,-tetrakis(4-carboxyphenyl)porphyrin, 62 was as prepared illustrated thusly, by thewhereby synthesis the carboxylate of carboxylated have beenmoieties benzoporph prepared were revealed byyrins Adler bystarting standard synthesis from ester an with ester-substitutedsaponificationester-functionalized benzaldehydesconditions isoindole after (Schemethe followed palladium 18) [107]. by insertion saponification A retro-Diels-Alder step (Scheme of the 17)reaction esters [106]. of [40 63]. with Tetracarboxylated concomitant palladiumsaponificationAn porphyrin introduction of the62 methylofwas esters prepared esters to the afforded β-positions thusly, octacarboxylate wherebyof a porphyrin the 64 carboxylatefrom. Protonation ester-substituted moietiesprovided building the were octaacid revealed blocks 65 by standardisthat also esteralso possible, precipitated saponification as illustrated under conditions bythese the conditions. synthesis after the of palladiumThe carboxylated water-solubility insertion benzoporph stepof the (Schemeyrins sodium starting 17 salt)[ 106 from64 ].was an Anester-functionalizeddetermined introduction to be 0.111 of isoindole esters M [107]. to(Scheme the β 18)-positions [107]. A retro-Diels-Alder of a porphyrin reaction from ester-substituted of 63 with concomitant building blockssaponification is also possible, of the as methyl illustrated esters afforded by the synthesis octacarboxylate of carboxylated 64. Protonation benzoporphyrins provided the octaacid starting 65 from that also precipitated under these conditions. The water-solubility of the sodium salt 64 was an ester-functionalized isoindole (Scheme 18)[107]. A retro-Diels-Alder reaction of 63 with concomitant determined to be 0.111 M [107]. saponification of the methyl esters afforded octacarboxylate 64. Protonation provided the octaacid

Molecules 2017, 22, 980 15 of 47

65 that also precipitated under these conditions. The water-solubility of the sodium salt 64 was determinedMolecules to 2017 be, 22 0.111, 980 M [107]. 15 of 46 Molecules 2017, 22, 980 15 of 46 Molecules 2017, 22, 980 15 of 46

Scheme 17. Carboxylated meso-aryl porphyrins, as described by the group of Skondra [106]. SchemeScheme 17. Carboxylated 17. Carboxylatedmeso meso-aryl-aryl porphyrins, porphyrins, as as described described by by the the group group of Skondra of Skondra [106].[ 106]. Scheme 17. Carboxylated meso-aryl porphyrins, as described by the group of Skondra [106].

Scheme 18. Carboxylated benzoporphyrins, as described by the group of Sugimoto [107]. Scheme 18. Carboxylated benzoporphyrins, as described by the group of Sugimoto [107]. SchemeScheme 18. Carboxylated 18. Carboxylated benzoporphyrins, benzoporphyrins, as descr describedibed by by the the group group of Sugimoto of Sugimoto [107]. [ 107].

Scheme 19. Porphyrin dimers and trimers bearing carboxylate groups in the meso-positions, as described Scheme 19. Porphyrin dimers and trimers bearing carboxylate groups in the meso-positions, as described Schemeby the group 19. Porphyrin of Kobuke dimers [108,109]. and trimers bearing carboxylate groups in the meso-positions, as described Schemeby the 19. groupPorphyrin of Kobuke dimers [108,109]. and trimers bearing carboxylate groups in the meso-positions, as by the group of Kobuke [108,109]. describedWater-soluble by the group acetylene-linked of Kobuke [108 bis(imidazolylporp,109]. hyrins) were prepared from starting materials Water-soluble acetylene-linked bis(imidazolylporphyrins) were prepared from starting materials bearingWater-soluble protected acid acetylene-linked functionalities. bis(imidazolylporp Thus, ester-functionalizedhyrins) were aldehyde prepared and from dipyrromethane starting materials were bearing protected acid functionalities. Thus, ester-functionalized aldehyde and dipyrromethane were Water-solublebearing protected acetylene-linked acid functionalities. bis(imidazolylporphyrins) Thus, ester-functionalized werealdehyde prepared and dipyrromethane from starting were materials bearing protected acid functionalities. Thus, ester-functionalized aldehyde and dipyrromethane were

Molecules 2017, 22, 980 16 of 47

Molecules 2017, 22, 980 16 of 46 condensed and oxidized to synthesize porphyrin 66 bearing ester-terminated alkyl chains in the meso-positions.condensed and The oxidized ester moieties to synthesize werecarried porphyrin through 66 bearing the entire ester-terminated synthesis ofalkyl the chains porphyrin in the dimer and themeso carboxylates-positions. The were ester onlymoieties deprotected were carried in thro theugh last the step entire (Scheme synthesis 19)[ of108 the]. porphyrin Using this dimer strategy, bulkyand bis(carboxylethyl)methyl the carboxylates were only substituents deprotected couldin the alsolast step be introduced(Scheme 19) to[108]. the Usingmeso-positions this strategy, early in the synthesisbulky bis(carboxylethy to furnish dimersl)methyl of substituents type 68 and could trimers also ofbe typeintroduced69, which to the showed meso-positions less aggregation early in in waterthe [109 synthesis]. to furnish dimers of type 68 and trimers of type 69, which showed less aggregation in Lindseywater [109]. and co-workers prepared carboxylated trans-AB porphyrins using a 2 + 2 dipyrromethane Lindsey and co-workers prepared carboxylated trans-AB porphyrins using a 2 + 2 dipyrromethane condensation strategy, using dipyrromethane 70 carrying a protected 2,4,6-triester-subsituted condensation strategy, using dipyrromethane 70 carrying a protected 2,4,6-triester-subsituted mesomeso-phenyl group (Scheme 20)[110]. The condensation of 70 and counterpart 71 in the presence of phenyl group (Scheme 20) [110]. The condensation of 70 and counterpart 71 in the presence of zinc zinc afforded the the zinc-porphyrin zinc-porphyrin triester triester 72, which72, which could could be saponified be saponiﬁed to afford to the afford tricarboxylic the tricarboxylic acid 73a. acid 73a. Along an an analogous analogous route, route, transtrans-AB-AB porphyrins porphyrins 73b and73b 73cand bearing73c bearing bioconjugatable bioconjugatable groups at groups the at the mesomeso-position-position opposite opposite the the solubilizing solubilizing groups groups were were prepared. prepared.

SchemeScheme 20. 20.Carboxylated Carboxylatedtrans trans-AB-AB porphyrins, porphyrins, as as described described by by the the group group of Lindsey of Lindsey [110]. [110 ].

To maximize the number of carboxylic acid groups introduced, carboxylic acid ester-terminated Todendritic maximize components the number can be of utilized, carboxylic often acid boun groupsd to the introduced, porphyrin carboxylicthrough amide acid linkages. ester-terminated For dendriticinstance, components treatment of can tetrarylporphyrin be utilized, acid often chloride bound 74 towith the dimethyl porphyrin iminodiacetate through or amide its second linkages. For instance,generation treatment dendrimer of analogue, tetrarylporphyrin followed by acid saponification chloride 74 of withthe esters, dimethyl afforded iminodiacetate the polyacid or its secondporphyrins generation 75a or dendrimer 75b, respectively analogue, (Scheme followed 21) [111]. by They saponification were purified of theby precipitation esters, afforded and filtration. the polyacid porphyrins1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic75a or 75b, respectively (Scheme 21) [111]. They acid were (DOTA) purified groups by were precipitation also introduced and filtration. to porphyrins through amide linkers on one or more meso-aryl groups of a porphyrin. These compounds 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) groups were also introduced to were used as multimodal heterometallic complexes for MRI/PET imaging applications [112,113]. porphyrins through amide linkers on one or more meso-aryl groups of a porphyrin. These compounds meso-Tetrakis(4-hydroxyphenyl)porphyrin (76) is a versatile starting material for the synthesis wereof used hydrophilic as multimodal derivatives heterometallic since the p-phenolic complexes oxygens for MRI/PET can react imaging with a applicationsvariety of solubilizing [112,113 ]. mesogroups.-Tetrakis(4-hydroxyphenyl)porphyrin A4-Porphyrin 76 is synthesized through (76 the) is aAdler versatile procedure, starting generally material as forits the4-methoxy synthesis of hydrophilicderivative, derivatives that can be since purified the andp-phenolic handled ea oxygenssily. It is cansubsequently react with deprotected a variety ofusing solubilizing BBr3 [14] (see groups. A4-Porphyrinalso below,76 Schemesis synthesized 23 and 47). through the Adler procedure, generally as its 4-methoxy derivative, that can beUsing puriﬁed tetraphenol and handled 76, Chen easily. and It co-workers is subsequently also synthe deprotectedsized porphyrins using BBr bearing3 [14] (see dendritic also below, Schemescarboxylate 23 and groups, 47). albeit their synthesis was less convergent than that of Mukhtar and co-workers [114], Usingsince the tetraphenol dendrimer generations76, Chen andwere co-workers built up on the also porphyrin synthesized core. porphyrinsThus, 76 was bearing converted dendritic to polyamine-derivatized porphyrin 77 in three steps. Reaction of the amines in 77 with bromoacetic carboxylate groups, albeit their synthesis was less convergent than that of Mukhtar and co-workers [114], since the dendrimer generations were built up on the porphyrin core. Thus, 76 was converted to polyamine-derivatized porphyrin 77 in three steps. Reaction of the amines in 77 with Molecules 2017, 22, 980 17 of 47

Molecules 2017, 22, 980 17 of 46 Molecules 2017, 22, 980 17 of 46 bromoaceticacid ethyl acid ester ethyl provided ester providedthe protected the porphyrin protected 78 porphyrin, followed78 by, followedhydrolysis by with hydrolysis TFA to give with the TFA to give theacidfree free acidethyl acid79 ester (Scheme79 provided(Scheme 22) [114] the 22)[ protectedthat114 was] that isolatedporphyrin was isolated by 78precipitation, followed by precipitation by(addition hydrolysis (addition of a withMeOH TFA of solution a MeOHto give of the solution 79 of 79freetoto Et Et acid2O).2O). 79 (Scheme 22) [114] that was isolated by precipitation (addition of a MeOH solution of 79 to Et2O).

SchemeScheme 21. Dendritic21. Dendritic carboxylated carboxylated porphyrins, porphyrins, as as described described by by the the group group of Mukhtar of Mukhtar [111]. [111 ]. Scheme 21. Dendritic carboxylated porphyrins, as described by the group of Mukhtar [111].

Scheme 22. Dendritic polycarboxylated porphyrins, as described by the group of Chen [114]. SchemeScheme 22. 22.Dendritic Dendritic polycarboxylated polycarboxylated porphyrins,porphyrins, as as described described byby the the group group of Chen of Chen [114]. [ 114].

Alkylation strategies have also been employed for the introduction of carboxylates. For instance, various carboxylated core-modiﬁed porphyrins were prepared by O-alkylation of the phenolic oxygens of a meso-4-hydroxyphenyl-substituted core-modiﬁed dithiaporphyrin. Like their aza-analogues, Molecules 2017, 22, 980 18 of 46

Molecules 2017, 22, 980 18 of 47 MoleculesAlkylation 2017, 22, 980 strategies have also been employed for the introduction of carboxylates. For instance,18 of 46 various carboxylated core-modified porphyrins were prepared by O-alkylation of the phenolic oxygensAlkylation of a meso strategies-4-hydroxyphenyl-substituted have also been employed core-modified for the introduction dithiaporphyrin. of carboxylates. Like their aza-analogues, For instance, the requisite core-modiﬁed porphyrins were synthesized with a methyl-ether protecting group in thevarious requisite carboxylated core-modified core-modified porphyrins porphyrinswere synthesized were preparedwith a methyl-ether by O-alkylation protecting of thegroup phenolic in the the p-position of one or more phenyl groups and deprotected using the standard BBr method. poxygens-position of of a mesoone or-4-hydroxyphenyl-substituted more phenyl groups and deprotected core-modified using dithiaporphyrin. the standard BBr Like3 method. their aza-analogues, The phenolic3 The phenolicoxygensthe requisite were oxygens core-modified then alkylated were then porphyrinswith alkylated ethyl bromoacetate. were with synthesized ethyl Saponification bromoacetate. with a methyl-ether of the Saponiﬁcationinstalled protecting esters furnishedgroup of the in installed thethe estersdithiaporphyrinp-position furnished of theone 81 dithiaporphyrinor bearing more phenyl carboxylic groups81 acidbearing and functi deprotectedonal carboxylic groups using (Scheme acid the functionalstandard 23) [115]. BBr groups3 method. (Scheme The phenolic 23)[115 ]. oxygens were then alkylated with ethyl bromoacetate. Saponification of the installed esters furnished the dithiaporphyrin 81 bearing carboxylic acid functional groups (Scheme 23) [115].

Scheme 23. Core-modified carboxylated porphyrin, as described by the group of Detty [115]. Scheme 23. Core-modified carboxylated porphyrin, as described by the group of Detty [115 ]. Diethylenetriamine-Scheme 23. Core-modifiedN,N,N′′ ,Ncarboxylated′′-tetraacetate porphyrin, (DTTA) as described groups bywere the groupalso ofintroduced Detty [115]. to meso 00 00 Diethylenetriamine-positions of a porphyriNn,N by,N alkylation,N -tetraacetate of meso-tetrakis(bromomethylpheny (DTTA) groups were alsol)porphyrin introduced [116]. The to meso positionsDTTA ofDiethylenetriamine- groups a porphyrin were introduced by alkylationN,N,N as′′,N protected′′ of-tetraacetatemeso -tetrakis(bromomethylphenyl)porphyrint-butyl (DTTA)esters and groups deprotected were usingalso standardintroduced [ 116conditions. ].to Themeso DTTA groupsThepositions were water-soluble introducedof a porphyri products asn by protected were alkylation purifiedt-butyl of by meso sequential esters-tetrakis(bromomethylpheny andcation deprotected and anion exchange usingl)porphyrin standardchromatography. [116]. conditions. The The water-solubleDTTAPrato groups and were productsco-workers introduced were also usedas purified protected an alkylation by t sequential-butyl strategy esterscation and to synthesizedeprotected and anion octacarboxylated using exchange standard chromatography. conditions. porphyrin Prato84The, starting water-soluble and co-workers from aproducts tetra(bromomethyl)-substit also were used pu anrified alkylation by sequentialuted strategy porphyrin. cation to synthesizeand Alkylation anion exchange octacarboxylated of porphyrin chromatography. 82 porphyrinwith Prato and co-workers also used an alkylation strategy to synthesize octacarboxylated porphyrin 84, startingdiethyl frommalonate a tetra(bromomethyl)-substituted afforded the tetramalonic ester-derivatized porphyrin. porphyrin Alkylation 83, of which porphyrin was saponified82 with diethylto free84, startingthe eight from carboxylate a tetra(bromomethyl)-substit moieties (Scheme 24)uted [97]. porphyrin. Octacarboxylate Alkylation 84 precipitated of porphyrin under 82 with the malonate afforded the tetramalonic ester-derivatized porphyrin 83, which was saponified to free the saponificationdiethyl malonate conditions afforded and the wastetramalonic isolated by ester-derivatized filtration to afford porphyrin the pure 83 product., which was saponified to eightfree carboxylate the eight moieties carboxylate (Scheme moieties 24)[ (Scheme97]. Octacarboxylate 24) [97]. Octacarboxylate84 precipitated 84 precipitated under the under saponification the conditionssaponification and was conditions isolated byand filtration was isolated to afford by filtration the pure to afford product. the pure product.

Scheme 24. Octacarboxylated porphyrin 84, as described by the group of Prato [97].

CarboxyphenylScheme 24.substituents Octacarboxylated can also porphyrin be directly 84, as introduceddescribed by to the the group meso of-positions Prato [97]. of synthetic Scheme 24. Octacarboxylated porphyrin 84, as described by the group of Prato [97]. chlorins and bacteriochlorins by Suzuki coupling of suitable meso-bromo-substituted porphyrins with Carboxyphenylboronic esters derived substituents from benzoiccan also acid. be directly Using theintroduced same Suzuki to the coupling meso-positions approach of syntheticthat was Carboxyphenylusedchlorins to introduce and bacteriochlorins substituentspyridyl substituents by can Suzuki also to bethecoupling directlymeso-position of introducedsuitable (cf. mesoScheme to-bromo-substituted the 12),meso chlorins-positions 85, porphyrins86 and of synthetic the chlorinsbacteriochlorinwith and boronic bacteriochlorins esters 87 (Figure derived 6) werefrom by Suzuki preparedbenzoic coupling acid. [91]. Us Theingof carboxylate the suitable same Suzuki functionalitymeso-bromo-substituted coupling was approach introduced that porphyrins in was the withfree boronicused acid to introduce form, esters eliminating derived pyridyl from substituentsthe need benzoic for theto acid. the utilization meso Using-position of the protecting same (cf. Scheme Suzuki groups. 12), coupling chlorins approach 85, 86 and that the was usedbacteriochlorin to introduce pyridyl87 (Figure substituents 6) were prepared to the [91].meso The-position carboxylate (cf. functionality Scheme 12), was chlorins introduced85, 86 in andthe the bacteriochlorinfree acid form,87 (Figureeliminating6) were the need prepared for the [ utilization91]. The carboxylate of protecting functionality groups. was introduced in the free acid form, eliminating the need for the utilization of protecting groups.

As well starting from meso-brominated precursors, the group of Anderson used a Sonogashira coupling strategy to functionalize the meso-positions of a PEGylated porphyrin dimer with carboxylate groups. meso-Dibromoporphyrin dimer 49 was coupled with 5-ethynyl-1,3-benzenedicarboxylic acid to form the tetracarboxylated water-soluble porphyrin dimer 88 (Scheme 25)[70]. Again, it is noteworthy that the acid functionality was introduced in unprotected form. Molecules 2017, 22, 980 19 of 46

Molecules 2017, 22, 980 19 of 47 Molecules 2017, 22, 980 19 of 46

Molecules 2017, 22, 980 19 of 46 Figure 6. Molecular structures of meso-carboxyphenyl-substituted chlorins 85 and 86, and bacteriochlorin 87.

As well starting from meso-brominated precursors, the group of Anderson used a Sonogashira coupling strategy to functionalize the meso-positions of a PEGylated porphyrin dimer with carboxylate groups.Figure meso 6. Molecular-Dibromoporphyrin structures of meso dimer-carboxyphenyl-substituted 49 was coupled with chlorins 5-ethynyl-1,3-benzenedicarboxylic 85 and 86, and bacteriochlorin 87. acid Figureto form 6. the Moleculartetracarboxylated structures water-soluble of meso-carboxyphenyl-substituted porphyrin dimer 88 (Scheme chlorins 25) [70].85 and Again,86, it and is bacteriochlorin 87. noteworthyAs well thatstarting the acidfrom functionality meso-brominated was introduced precursors, in the unprotected group of Anderson form. used a Sonogashira coupling strategy to functionalize the meso-positions of a PEGylated porphyrin dimer with carboxylate HO2C

groups. meso-Dibromoporphyrin dimer 49 was coupled with 5-ethynyl-1,3-benzenedicarboxylicO(CH2CH2O)3CH3 acid

to form theAr tetracarboxylatedAr water-soluble porphyrin dimer 88 (SchemeAr = 25) [70]. Again, it is HO2C noteworthy that the acid functionality wasPd introduced(dba) , CuI, in unprotected form. N N N N 2 3 Figure 6. Molecular structures of meso-carboxyphenyl-substitutedPPh3, DMF, Et3N chlorins 85 and 86, and bacteriochlorin 87. Br Zn Zn Br HO C N N N N 2 Ar Ar As well starting from meso-brominated precursors, the group of Anderson usedO(CH2CH a2O) Sonogashira3CH3 + – – + Ar Ar Na O2C CO2 Na Ar Ar N N Ar = N N coupling strategy to49 functionalize the meso-positionsHO C of a PEGylated porphyrin dimer with carboxylate 2 Zn Zn Pd (dba) , CuI, groups.N mesoN-DibromoporphyrinN N dimer 49 was2 3coupled with 5-ethynyl-1,3-benzenedicarboxylic acid PPh , DMF, Et N N N N N + – 3 3 CO –Na+ to Brform theZn tetracarboxylatedZn water-solubleBr Na O2C porphyrin dimer 88 (Scheme 25) [70]. Again,2 it is N N N N Ar Ar Ar Ar noteworthy that the acid functionality was introduced in unprotected88 form. + – – + Na O2C CO2 Na Ar Ar N N N N Scheme 25. Carboxylated49 bis-acetylene linked porphyrin dimers, as described by the group of Scheme 25. Carboxylated bis-acetylene linkedHO2C porphyrinZn dimers, as describedZn by the group of Anderson [70]. dba = dibenzylacetone. N N N N O(CH2CH2O)3CH3 + – – + Anderson [70]. dba = dibenzylacetone. Na O2C CO2 Na Ar Ar Ar = HO2C Ar Ar 88 Pd (dba) , CuI, N N N N 2 3 Functionalization of the β-position ofPPh bacteriochlorins3, DMF, Et3N with carboxyphenyl groups was also BrSchemeZn 25. Carboxylated Znbis-acetyleneBr linked porphyrin dimers, as described by the group of N N N N Ar Ar achievedAnderson by Suzuki [70]. dba coupling, = dibenzylacetone. albeit this method required the use of protected boronic ester + – – + Na O2C CO2 Na carboxylates [117Ar ]. Thus, β-dibromoporphyrinAr 89 wasN functionalizedN usingN N the boronic ester of 49 the t-butyl ester-protected 3,5-carboxyphenyl substituentsZn (Scheme 26).Zn The protecting groups N N N N + – CO –Na+ were removed at the last step of the synthesisNa O2C by acid treatment. Furthermore, the option2 for Ar Ar bioconjugation was demonstrated in these systems by Suzuki coupling88 of a meso-bromobacteriochlorin, generatedScheme by regioselective 25. Carboxylated bromination bis-acetylene linked of the porphyrin parent bacteriochlorin,dimers, as described to by produce the group hydrophilicof tetracarboxyl-bacteriochlorinAnderson [70]. dba = dibenzylacetone.94 [117].

Scheme 26. Tetracarboxybacteriochlorins, as described by the group of Lindsey [117].

Functionalization of the β-position of bacteriochlorins with carboxyphenyl groups was also achieved by Suzuki coupling, albeit this method required the use of protected boronic ester carboxylatesScheme [117]. 26.Thus, Tetracarboxybacteriochlorins, β-dibromoporphyrin 89 as was descr functionalizedibed by the group using of Lindsey the boronic [117]. ester of the

Functionalization of the β-position of bacteriochlorins with carboxyphenyl groups was also achieved by Suzuki coupling, albeit this method required the use of protected boronic ester carboxylates [117]. Thus, β-dibromoporphyrin 89 was functionalized using the boronic ester of the

SchemeScheme 26. 26.Tetracarboxybacteriochlorins, Tetracarboxybacteriochlorins, as descr describedibed by by the the group group of ofLindsey Lindsey [117]. [117 ].

Functionalization of the β-position of bacteriochlorins with carboxyphenyl groups was also achieved by Suzuki coupling, albeit this method required the use of protected boronic ester carboxylates [117]. Thus, β-dibromoporphyrin 89 was functionalized using the boronic ester of the

Molecules 2017, 22, 980 20 of 46

t-butyl ester-protected 3,5-carboxyphenyl substituents (Scheme 26). The protecting groups were Molecules 2017, 22, 980 20 of 47 removed at the last step of the synthesis by acid treatment. Furthermore, the option for bioconjugation was demonstrated in these systems by Suzuki coupling of a meso-bromobacteriochlorin, generated 3.2. Sulfonatedby regioselective Porphyrins bromination of the parent bacteriochlorin, to produce hydrophilic tetracarboxyl- bacteriochlorin 94 [117]. Sulfonation of meso-tetraphenylporphyrin proceeds regioselectively at the para-positions of the3.2.meso Sulfonated-phenyl Porphyrins rings [118]. This reaction led to the earliest examples of water-soluble meso-tetraaryl-porphyrinsSulfonation of meso-tetraphenylporphyrin [40]. A number of sulfonatedproceeds regioselectively A4 porphyrins at the were para-positions prepared of by the direct sulfonationmeso-phenyl methods rings [[118].40], and This are reaction commercially led to the available earliest examples [58]. However, of water-soluble this solubilization meso-tetraaryl- strategy has drawbacks,porphyrins not[40]. the A number least of of which sulfonated are the A4 harsh porphyrins reaction were conditions prepared (conc.by direct H 2sulfonationSO4, ∆) required methods for the sulfonation[40], and step, are commercially and the difficulty available in purifying [58]. However, the target this solubilization compound. Onstrategy the otherhas drawbacks, hand, sulfonation not readilythe leadsleast of to which the solubilization are the harsh reaction of porphyrins conditions in (conc. aqueous H2SO media.4, ∆) required Interestingly, for the sulfonation the porphyrin step, is and the difficulty in purifying the target compound. On the other hand, sulfonation readily leads to protonated during the sulfonation step and is thus protected by the dicationic charge from getting the solubilization of porphyrins in aqueous media. Interestingly, the porphyrin is protonated during sulfonated at the β-positions along an electrophilic aromatic substitution pathway, in contrast with the the sulfonation step and is thus protected by the dicationic charge from getting sulfonated at the regioselectiveβ-positionsβ along-sulfonation an electrophilic of the less aromatic basic substitution corroles using pathway, chlorosulfonic in contrast acid with [ 119the –regioselective121]. Oneβ-sulfonation particular of the challenge less basic corroles faced byusing using chlorosulfonic sulfonation acid procedures[119–121]. is the incorporation of other functionalOne particular groups challenge since theyfaced may by using be incompatible sulfonation procedures with the is harsh the incorporation sulfonation of conditions. other Thefunctional sulfonation groups step since is they often may employed be incompatible directly with the after harsh porphyrin sulfonation formation, conditions. The then sulfonation subsequent modificationstep is often of employed the porphyrin directly is after performed. porphyrin The formation, drawback then of subsequent this strategy modification is the difficulty of the porphyrin in handling and purificationis performed. of The the drawback sulfonated of porphyrins.this strategy is the difficulty in handling and purification of the Despitesulfonated these porphyrins. disadvantages, the traditional direct sulfonation method was employed by Pillai and Despite these disadvantages, the traditional direct sulfonation method was employed by Pillai co-workers to regioselectively introduce sulfonate groups to the meso-p-phenyl positions of N-confused and co-workers to regioselectively introduce sulfonate groups to the meso-p-phenyl positions of N 95 porphyrinsN-confused (Scheme porphyrins 27)[122 (Scheme]. Sulfonation 27) [122]. Sulfonation of -confused of N-confused porphyrin porphyrinby treatment 95 by treatment with Hwith2SO 4 at elevatedH2SO temperature4 at elevated temperature over several over hours several afforded hours theafforded tetrasulfonated the tetrasulfonated porphyrin porphyrin96 that 96 wasthat was tested as a photosensitizertested as a photosensitizer for PDT [122 for]. PDT The [122]. product The wasproduct purified was purified by precipitation by precipitation and continuousand continuous Soxhlet extractionSoxhlet with extraction MeOH. with No MeOH. further No functionalizationsfurther functionalizations of this of this porphyrin porphyrin derivative derivative werewere reported.

SchemeScheme 27. 27.Sulfonated SulfonatedN -confusedN-confused porphyrin,porphyrin, as as described described by by the the group group of Pillai of Pillai [122]. [122 ].

Likewise, asymmetric meso-aryl porphyrins were also subjected to sulfonation reactions. For Likewise,instance, A3B asymmetric porphyrin mesomeso-trisphenyl-4-pyridylporphyrin,-aryl porphyrins were alsomade subjected by mixed aldehyde to sulfonation condensation, reactions. For instance,could be trisulfonated A3B porphyrin using oleummeso -trisphenyl-4-pyridylporphyrin,at 80 °C [123]. The pure product was madeobtained by by mixedprecipitation aldehyde condensation,and centrifugation could be after trisulfonated neutralization using of the oleum acid. atThe 80 pyridyl◦C[123 moiety]. The could pure then product be functionalized was obtained by precipitationwith a platinum and centrifugation complex for study after neutralizationas a tumor targeting of the photosensitizer. acid. The pyridyl The moietygroup of could Lippard then be functionalizedprepared the with A3B aporphyrin platinum meso complex-trisphenyl-(2,6-nitrophenyl)porphyrin for study as a tumor targeting 97 photosensitizer. (Scheme 28). Reduction The group of the nitro group afforded the 2,6-diaminophenyl porphyrin 98 that was subjected to sulfonation. of Lippard prepared the A B porphyrin meso-trisphenyl-(2,6-nitrophenyl)porphyrin 97 (Scheme 28). The water-soluble product3 99 was purified and isolated by reverse phase chromatography (RP-18). The Reduction of the nitro group afforded the 2,6-diaminophenyl porphyrin 98 that was subjected to purified free amine could then be functionalized with DPA for its use as a Zn2+ chemosensor [124]. sulfonation.Furthermore, The water-soluble the manganese product complex99 of 100was was purified prepared and and isolated used as by a reversedual function phase contrast chromatography agent 2+ (RP-18).for the The fluorescence purified imaging free amine of Zn2 could and MRI then in biological be functionalized contexts [124]. with DPA for its use as a Zn chemosensor [124]. Furthermore, the manganese complex of 100 was prepared and used as a dual function contrast agent for the fluorescence imaging of Zn2 and MRI in biological contexts [124]. As the previous examples have shown, some functionalities tolerate the sulfonation conditions. Surprisingly, this is also the case for isoindoline nitroxide-functionalized A3B porphyrin 101. All phenyl substituents could be sulfonated by treatment with H2SO4 with retention of the isoindoline nitroxide (Scheme 29), albeit the yield for the water-soluble final product 102 was low (~30%) [125]. Molecules 2017, 22, 980 21 of 46

Molecules 2017, 22, 980 21 of 47 Molecules 2017, 22, 980 21 of 46

Scheme 28. Sulfonated A3B porphyrin bearing DPA substituents for fluorescence sensing of Zn2+, as described by the group of Lippard [124].

As the previous examples have shown, some functionalities tolerate the sulfonation conditions. Surprisingly, this is also the case for isoindoline nitroxide-functionalized A3B porphyrin 101. All Scheme 28. Sulfonated A3B porphyrin bearing DPA substituents for fluorescence sensing of Zn2+, as2+ Scheme 28. Sulfonated A3B porphyrin bearing DPA substituents for ﬂuorescence sensing of Zn , as phenyldescribed substituents by the groupcould of be Lippard sulfonated [124]. by treatment with H2SO4 with retention of the isoindoline describednitroxide (Scheme by the group 29), albeit of Lippard the yiel [124d for]. the water-soluble final product 102 was low (~30%) [125]. As the previous examples have shown, some functionalities tolerate the sulfonation conditions. Surprisingly, this is also the case for isoindoline nitroxide-functionalized A3B porphyrin 101. All phenyl substituents could be sulfonated by treatment with H2SO4 with retention of the isoindoline nitroxide (Scheme 29), albeit the yield for the water-soluble final product 102 was low (~30%) [125].

Scheme 29. Sulfonated isoindoline nitroxide-functionalized A3B porphyrin, as described by the group Scheme 29. Sulfonated isoindoline nitroxide-functionalized A3B porphyrin, as described by the group of Yang [125]. of Yang [125]. A chlorosulfonation method has been used for the introduction of sulfonic acid groups to a Anumber chlorosulfonation of halogenated meso method-aryl porphyrins has been by used the group for theof Wy introductionatt and co-workers of sulfonic (Scheme 30) acid [126]. groups Scheme 29. Sulfonated isoindoline nitroxide-functionalized A3B porphyrin, as described by the group to aTreatment numberof Yang of of [125]. chlorinated halogenated porphyrinmeso 103-aryl, for example, porphyrins with chlorosulfonic by the group acid afforded of Wyatt chlorosulfonation and co-workers (Schemeproduct 30)[ 104126 that]. Treatment was hydrolyzed of chlorinated by suspension porphyrin in H2O to103 provide, for example, the corresponding with chlorosulfonic sulfonic acid acid product 105. Alternatively, the chlorosulfonate could also be converted to sulfonamide derivatives by afforded chlorosulfonationA chlorosulfonation productmethod has104 beenthat used was hydrolyzedfor the introduction by suspension of sulfonic in acid H2O groups to provide to a the reaction with amines [126]. The corresponding chlorin and bacteriochlorin 106 and 107, respectively, correspondingnumber of halogenated sulfonic acid meso product-aryl porphyrins105. Alternatively, by the group the of chlorosulfonate Wyatt and co-workers could (Scheme also be 30) converted [126]. to were made by diimide reduction of the sulfonated porphyrin 105, and were tested as photosensitizers sulfonamideTreatment derivatives of chlorinated by porphyrin reaction with103, for amines example, [126 with]. The chlorosulfonic corresponding acid afforded chlorin chlorosulfonation and bacteriochlorin productfor the PDT 104 of that tumors was (Schemehydrolyzed 30) [127].by suspension in H2O to provide the corresponding sulfonic acid 106 and 107, respectively, were made by diimide reduction of the sulfonated porphyrin 105, and were product 105. Alternatively, the chlorosulfonate could also be converted to sulfonamide derivatives by testedreaction as photosensitizers with amines [126]. for theThe PDTcorresponding of tumors chlorin (Scheme and 30bacteriochlorin)[127]. 106 and 107, respectively, Thewere attachmentmade by diimide of sulfonatedreduction of groupsthe sulfonated to the porphyrinβ-positions 105, and of were a tetrapyrrolic tested as photosensitizers macrocycle is an alternativefor the PDT method of tumors toward (Scheme the 30) generation[127]. of hydrophilic sulfonated derivatives. This approach was applied to the generation of alkylsulfonated bacteriochlorins [128]. For example, sulfonated bacterio-chlorophyll derivatives were prepared by reaction of Pd-bacteriopheophorbide (108) with homo-taurine (Scheme 31)[128]. Treatment of either 109 or the sulfo-NHS ester 110 with a second equivalent of homotaurine also yielded the bis-sulfonated product 111 (with the trisulfonated compound arising from imine formation with the β-acetyl group as a minor product). Bacteriochlorin 112M could also prepared using a similar procedure using taurine as the nucleophile. All of the sulfonated derivatives were found to possess high solubility in water (up to 40 mg/mL) [129]. Molecules 2017, 22, 980 22 of 47

The products were either puriﬁed by HPLC (MeOH/phosphate-buffer solvent systems) or by silica gel chromatographyMolecules 2017, 22 (4:1, 980 CHCl3:MeOH). 22 of 46

Scheme 30. Chlorosulfonated porphyrins and their hydrolysis and reduction products, as described Scheme 30. Chlorosulfonated porphyrins and their hydrolysis and reduction products, as described by by the group of Wyatt [126]. DBO = 1,4-diazobicyclo[2.2.2]octane. the group of Wyatt [126]. DBO = 1,4-diazobicyclo[2.2.2]octane. Molecules 2017, 22, 980 23 of 46 The attachment of sulfonated groups to the β-positions of a tetrapyrrolic macrocycle is an alternative method toward the generation of hydrophilic sulfonated derivatives. This approach was applied to the generation of alkylsulfonated bacteriochlorins [128]. For example, sulfonated bacteriochlorophyll derivatives were prepared by reaction of Pd-bacteriopheophorbide (108) with homotaurine (Scheme 31) [128]. Treatment of either 109 or the sulfo-NHS ester 110 with a second equivalent of homotaurine also yielded the bis-sulfonated product 111 (with the trisulfonated compound arising from imine formation with the β-acetyl group as a minor product). Bacteriochlorin 112M could also prepared using a similar procedure using taurine as the nucleophile. All of the sulfonated derivatives were found to possess high solubility in water (up to 40 mg/mL) [129]. The products were either purified by HPLC (MeOH/phosphate-buffer solvent systems) or by silica gel chromatography (4:1 CHCl3:MeOH). Sulfonate functionalities may also be introduced at a late stage in the porphyrin synthesis by transition metal-mediated cross-coupling strategies. For instance, Anderson and co-workers introduced sulfonate groups to the meso-positions of a meso-brominated PEGylated conjugated porphyrin dimer using a Suzuki coupling with a sulfonated arylboronic acid, a strategy similar to the introduction of pyridine functionalities described above (cf. Scheme 13) [70]. The tetrasulfonated porphyrin dimer 113 (Figure 7) was purified using semi-preparative reverse-phase HPLC.

Scheme 31. Sulfonated Pd-bacteriopheophorbide, as described by the group of Scherz [129]. EDC = Scheme 31. Sulfonated Pd-bacteriopheophorbide, as described by the group of Scherz [129]. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.Figure 7. Molecular structure of sulfonated biporphyrin 113. 3.3. Porphyrins with Phosphate/Phosphonate Functional Groups

The introduction of alkylphosphonate functional groups to the periphery of a porphyrin is another strategy to impart hydrophilicity to porphyrins and hydroporphyrins. Phosphate groups have also been employed, but because of the increased hydrolytic lability of the phosphate group, only rarely. Alkyl phosphonates have been introduced to the porphyrin by modification of a porphyrin or by the synthesis of the porphyrin macrocycle with protected phosphonate/phosphate or alcohol building blocks. Deprotection and subsequent modification of the porphyrin furnished the water- soluble phosphonated derivatives. One of the first examples of porphyrins bearing phosphonate groups was introduced by the group of Montforts [130]. They prepared water-soluble metalloporphyrins by phosphonation of the primary alkyl alcohols in deuteroporphyrin derivative 114M (Scheme 32) [130]. Their strategy involved the conversion of the alcohols in 114M to brominated derivative 115M, followed by reaction with P(OSiMe3)3, and subsequent hydrolysis of the intermediate with MeOH/H2O to afford phosphonate 116M. The free phosphonate functional groups were used to attach these derivatives to electrode surfaces [130]. Using a similar strategy, diphosphonated chlorin derivatives rac-117 and rac-118 were also prepared (Scheme 32). While the requisite alkyl alcohols for phosphonation in 114M were generated by functional group manipulation of the propionic acid side chains present in the natural product precursors, the requisite alcohols can also be introduced (in free or protected form) at the porphyrin synthesis stage. For instance, Lindsey and co-workers prepared trans-AB porphyrin 119 by using a dipyrromethane precursor bearing two t-butyldimethylsilyl-(TBDMS) protected hydroxyl groups (Scheme 33) [131]. After removal of the protecting groups, the hydroxyl groups could be derivatized in a similar manner as described by Montforts [130] to provide the protected phosphonate ester 120. An ester hydrolysis revealed the free phosphonate groups, conveying water-solubility. The corresponding zinc complexes were also prepared.

Molecules 2017, 22, 980 22 of 46

Scheme 30. Chlorosulfonated porphyrins and their hydrolysis and reduction products, as described by the group of Wyatt [126]. DBO = 1,4-diazobicyclo[2.2.2]octane.

The attachment of sulfonated groups to the β-positions of a tetrapyrrolic macrocycle is an alternative method toward the generation of hydrophilic sulfonated derivatives. This approach was applied to the generation of alkylsulfonated bacteriochlorins [128]. For example, sulfonated bacteriochlorophyll derivatives were prepared by reaction of Pd-bacteriopheophorbide (108) with homotaurine (Scheme 31) [128]. Treatment of either 109 or the sulfo-NHS ester 110 with a second equivalent of homotaurine also yielded the bis-sulfonated product 111 (with the trisulfonated compound arising from imine formation with the β-acetyl group as a minor product). Bacteriochlorin 112M could also Moleculesprepared2017, 22 using, 980 a similar procedure using taurine as the nucleophile. All of the sulfonated derivatives23 of 47 were found to possess high solubility in water (up to 40 mg/mL) [129]. The products were either purified by HPLC (MeOH/phosphate-buffer solvent systems) or by silica gel chromatography (4:1 CHClSulfonate3:MeOH). functionalities may also be introduced at a late stage in the porphyrin synthesis by transitionSulfonate metal-mediated functionalities cross-couplingmay also be introduced strategies. at a late For stage instance, in the Andersonporphyrin synthesis and co-workers by introducedtransition sulfonate metal-mediated groups cross-coupling to the meso strategies.-positions For ofinstance, a meso Anderson-brominated and co-workers PEGylated introduced conjugated sulfonate groups to the meso-positions of a meso-brominated PEGylated conjugated porphyrin dimer porphyrin dimer using a Suzuki coupling with a sulfonated arylboronic acid, a strategy similar using a Suzuki coupling with a sulfonated arylboronic acid, a strategy similar to the introduction of to the introduction of pyridine functionalities described above (cf. Scheme 13)[70]. The tetrasulfonated pyridine functionalities described above (cf. Scheme 13) [70]. The tetrasulfonated porphyrin dimer porphyrin113 (Figure dimer 7) 113was (Figurepurified7 using) was semi-prepa puriﬁed usingrative semi-preparative reverse-phase HPLC. reverse-phase HPLC.

FigureFigure 7. Molecular 7. Molecular structure structure of of sulfonated sulfonatedbiporphyrin biporphyrin 113113. .

3.3. Porphyrins with Phosphate/Phosphonate Functional Groups The introduction of alkylphosphonate functional groups to the periphery of a porphyrin is another strategy to impart hydrophilicity to porphyrins and hydroporphyrins. Phosphate groups have also been employed, but because of the increased hydrolytic lability of the phosphate group, only rarely. Alkyl phosphonates have been introduced to the porphyrin by modification of a porphyrin or by the synthesis of the porphyrin macrocycle with protected phosphonate/phosphate or alcohol building blocks. Deprotection and subsequent modification of the porphyrin furnished the water-soluble phosphonated derivatives. One of the first examples of porphyrins bearing phosphonate groups was introduced by the group of Montforts [130]. They prepared water-soluble metalloporphyrins by phosphonation of the primary alkyl alcohols in deuteroporphyrin derivative 114M (Scheme 32)[130]. Their strategy involved the conversion of the alcohols in 114M to brominated derivative 115M, followed by reaction with P(OSiMe3)3, and subsequent hydrolysis of the intermediate with MeOH/H2O to afford phosphonate 116M. The free phosphonate functional groups were used to attach these derivatives to electrode surfaces [130]. Using a similar strategy, diphosphonated chlorin derivativesMolecules rac2017-117, 22, 980and rac-118 were also prepared (Scheme 32). 24 of 46

Scheme 32. Phosphonated β-alkyl porphyrin derivatives, as described the group of Montforts [130]. Scheme 32. Phosphonated β-alkyl porphyrin derivatives, as described the group of Montforts [130]. Along analogous pathways, trans-AB porphyrins bearing amino (121c), acetamido (121d), and iodoacetamido (121e) bioconjugatable tethers at the meso-phenyl position opposite the solubilizing group also became accessible (Scheme 33) [132]. This approach is suitable for the synthesis of phosphonated chlorins, synthesized by using dipyrromethane building block 123, bearing two protected alcohols (Scheme 34) [133]. After condensation of 122 and 123, the benzyl ether protecting groups in 124 were removed, and the alcohols were brominated and phosphonated. The phosphonate ester was then treated with TMS-Br to furnish the free phosphonates.

Scheme 33. trans-AB Porphyrins bearing swallowtail phosphonate motifs, as described by the group of Lindsey [131,132].

Molecules 2017, 22, 980 24 of 46

Molecules 2017, 22, 980 24 of 47

While the requisite alkyl alcohols for phosphonation in 114M were generated by functional group manipulation of the propionic acid side chains present in the natural product precursors, the requisite alcohols can also be introduced (in free or protected form) at the porphyrin synthesis stage. For instance, Lindsey and co-workers prepared trans-AB porphyrin 119 by using a dipyrromethane precursor bearing two t-butyldimethylsilyl-(TBDMS) protected hydroxyl groups (Scheme 33)[131]. After removal of the protecting groups, the hydroxyl groups could be derivatized in a similar manner as described by Montforts [130] to provide the protected phosphonate ester 120. An ester hydrolysis revealed the free phosphonate groups, conveying water-solubility. The corresponding zinc complexes were alsoScheme prepared. 32. Phosphonated β-alkyl porphyrin derivatives, as described the group of Montforts [130]. Along analogous pathways, trans-AB porphyrins bearing amino (121c), acetamido (121d), and iodoacetamidoAlong analogous (121e) pathways, bioconjugatable trans-AB tethers porphyrins at the bearingmeso-phenyl amino position (121c), acetamido opposite ( the121d solubilizing), and groupiodoacetamido also became (121e accessible) bioconjugatable (Scheme tethers 33)[132 at the]. Thismeso-phenyl approach position is suitable opposite for thethe solubilizing synthesis of phosphonatedgroup also chlorins,became accessible synthesized (Scheme by using33) [132]. dipyrromethane This approach is building suitable blockfor the123 synthesis, bearing of two phosphonated chlorins, synthesized by using dipyrromethane building block 123, bearing two protected alcohols (Scheme 34)[133]. After condensation of 122 and 123, the benzyl ether protecting protected alcohols (Scheme 34) [133]. After condensation of 122 and 123, the benzyl ether protecting groupsgroups in 124 in 124were were removed, removed, and and the the alcohols alcohols were brominated brominated and and phosphonated. phosphonated. The Thephosphonate phosphonate esterester was was then then treated treated with with TMS-Br TMS-Br to to furnish furnish thethe free phosphonates.

SchemeScheme 33. trans 33. trans-AB-AB Porphyrins Porphyrins bearing bearing swallowtail swallowtail phosph phosphonateonate motifs, motifs, as descr as describedibed by the by group the group of Lindsey [131,132]. of Lindsey [131,132]. Molecules 2017, 22, 980 25 of 46 Lindsey and co-workers also prepared trans-AB porphyrins incorporating phosphate groups, though in this instance they started with a dipyrromethane precursor already bearing phosphate esters (Scheme 35) [131]. Hydrolysis of the protected phosphate groups afforded the free phosphate groups.

SchemeScheme 34. Synthetic 34. Synthetic chlorins chlorins bearing bearing phosphonate phosphonate swallowtail motifs, motifs, as asdescribed described by the by group the group of of LindseyLindsey [133 ].[133]. TMPi TMPi = 2,2,6,6-tetramethylpiperidine. = 2,2,6,6-tetramethylpiperidine.

Scheme 35. Porphyrin bearing phosphate swallowtail motif, as described by the group of Lindsey [131].

Phosphonate groups can also be introduced to the porphyrin by starting with dipyrromethane precursors bearing protected phosphonate functional groups. Using this strategy, trans-AB porphyrin 130 (Figure 8) was synthesized by condensation using a dipyrromethane precursor carrying an 2,6-diphosphonated aryl ring that projects the solubilizing groups above and below the plane of the macrocycle target (cf. Scheme 35) [134]. Hydrolysis of the phosphonate esters and saponification affords the trans-AB porphyrin bearing both the phosphonate solubilization groups and a carboxylic acid bioconjugatable tether. Using a similar strategy as for chlorin 125, this 2,6-aryl-phosphonate motif was also incorporated into chlorin 131 [133]. Again, the Suzuki coupling strategy of β- dibromobacteriochlorins proved versatile enough to be applicable to the introduction of β-aryl- phosphonate groups (cf. Scheme 6) to afford, after hydrolysis of the phosphonate esters, water- soluble bacteriochlorin 132.

Figure 8. Molecular structures of phosphonated porphyrin 130, chlorin 131, and bacteriochlorin 132.

Molecules 2017, 22, 980 25 of 46

Molecules 2017, 22, 980 25 of 47

Lindsey and co-workers also prepared trans-AB porphyrins incorporating phosphate groups, though in this instance they started with a dipyrromethane precursor already bearing phosphate esters Scheme 34. Synthetic chlorins bearing phosphonate swallowtail motifs, as described by the group of (Scheme 35Lindsey)[131 [133].]. Hydrolysis TMPi = 2,2,6,6-tetramethylpiperidine. of the protected phosphate groups afforded the free phosphate groups. Scheme 34. Synthetic chlorins bearing phosphonate swallowtail motifs, as described by the group of Lindsey [133]. TMPi = 2,2,6,6-tetramethylpiperidine.

Scheme 35. Porphyrin bearing phosphate swallowtail motif, as described by the group of Lindsey [131]. Scheme 35. Porphyrin bearing phosphate swallowtail motif, as described by the group of Lindsey [131]. PhosphonateScheme 35. Porphyrin groups bearing can also phosphate be introduced swallowtail to motif,the porphyrin as described by by starting the group with of Lindsey dipyrromethane [131]. precursorsPhosphonate bearing groups protected can phosphonate also be introduced functional to groups. the porphyrin Using this strategy, by starting trans with-AB porphyrin dipyrromethane 130 precursors(FigurePhosphonate bearing8) was protectedsynthesized groups can phosphonate alsoby condensationbe introduced functional usingto the groups. porphyrina dipyrromethane Using by thisstarting strategy, precursor with dipyrromethanetrans carrying-AB porphyrin an 130 (Figure2,6-diphosphonatedprecursors8) bearing was synthesized protected aryl ring phosphonate that by projects condensation functional the solubilizing groups. using groupsUsing a dipyrromethane this above strategy, and belowtrans-AB precursor the porphyrin plane of carrying the130 an 2,6-diphosphonatedmacrocycle(Figure 8) targetwas synthesized(cf. arylScheme ring by35) that condensation[134]. projects Hydrolys the usingis solubilizing of thea dipyrromethane phosphonate groups esters above precursor and and saponification belowcarrying the an plane of theaffords2,6-diphosphonated macrocycle the trans-AB target porphyrinaryl (cf.ring that bearing Scheme projects both 35 the )[the solubilizing134 phosphonate]. Hydrolysis groups solubilization above of theand groups phosphonatebelow and the aplane carboxylic esters of the and macrocycle target (cf. Scheme 35) [134]. Hydrolysis of the phosphonate esters and saponification saponiﬁcationacid bioconjugatable affords the tether.trans Using-AB porphyrin a similar strategy bearing as both for chlorin the phosphonate 125, this 2,6-aryl-phosphonate solubilization groups motifaffords was the alsotrans -ABincorporated porphyrin into bearing chlorin both 131 the phosphonate[133]. Again, solubilizationthe Suzuki coupling groups and strategy a carboxylic of β- and a carboxylic acid bioconjugatable tether. Using a similar strategy as for chlorin 125, this dibromobacteriochlorinsacid bioconjugatable tether. proved Using versatile a similar enough strategy to beas forapplicable chlorin to125 the, this introduction 2,6-aryl-phosphonate of β-aryl- 2,6-aryl-phosphonate motif was also incorporated into chlorin 131 [133]. Again, the Suzuki coupling phosphonatemotif was also groups incorporated (cf. Scheme into 6) chlorin to afford, 131 af[133].ter hydrolysis Again, the of Suzukithe ph osphonatecoupling strategyesters, water- of β- strategysolubledibromobacteriochlorins of βbacteriochlorin-dibromobacteriochlorins 132 proved. versatile proved enough versatile to be enough applicable to beto applicablethe introduction to the of introduction β-aryl- of β-aryl-phosphonatephosphonate groups groups (cf. Scheme (cf. Scheme6) to afford,6) to af afford,ter hydrolysis after hydrolysis of the phosphonate of the phosphonate esters, water- esters, water-solublesoluble bacteriochlorin bacteriochlorin 132. 132.

Figure 8. Molecular structures of phosphonated porphyrin 130, chlorin 131, and bacteriochlorin 132.

FigureFigure 8. Molecular 8. Molecular structures structures of of phosphonated phosphonated porphyrin 130130, chlorin, chlorin 131131, and, and bacteriochlorin bacteriochlorin 132. 132.

4. Water-Soluble Porphyrins with Neutral Groups

4.1. PEGylated Porphyrins PEGylation has emerged as a strategy for the preparation of neutral water-soluble porphyrins and hydroporphyrins. It has many benefits over traditional means using ionic groups. For instance, PEGylation strategies are more flexible with respect to where in the synthetic sequence they are introduced. This is because the PEG functional group is not very reactive once installed. Unwanted reactivity to form oligomeric species is also suppressed by using heterobifunctional PEG chains, in which one end of the PEG chain often has a methyl cap. PEGylated porphyrins are also much more amenable to traditional aqueous work-up conditions, as they may partition favorably in organic solvents such as CH2Cl2 and EtOAc [135,136]. Often times PEGylated porphyrins can be purified by normal silica-gel chromatography using polar solvents [14,137–139]. Molecules 2017, 22, 980 26 of 46

4. Water-Soluble Porphyrins with Neutral Groups

4.1. PEGylated Porphyrins PEGylation has emerged as a strategy for the preparation of neutral water-soluble porphyrins and hydroporphyrins. It has many benefits over traditional means using ionic groups. For instance, PEGylation strategies are more flexible with respect to where in the synthetic sequence they are introduced. This is because the PEG functional group is not very reactive once installed. Unwanted reactivity to form oligomeric species is also suppressed by using heterobifunctional PEG chains, in which one end of the PEG chain often has a methyl cap. PEGylated porphyrins are also much more Moleculesamenable2017, 22 ,to 980 traditional aqueous work-up conditions, as they may partition favorably in organic26 of 47 solvents such as CH2Cl2 and EtOAc [135,136]. Often times PEGylated porphyrins can be purified by normal silica-gel chromatography using polar solvents [14,137–139]. 4.1.1. Porphyrinoid Macrocycle Total Synthesis Using PEGylated Building Blocks 4.1.1. Porphyrinoid Macrocycle Total Synthesis Using PEGylated Building Blocks Despite these advantages, the multistep manipulation of porphyrins with PEG-groups present throughoutDespite the synthesisthese advantages, is relatively the multistep rare. For manipula instance,tion of Brunner porphyrins and wi co-workersth PEG-groups presented present such throughout the synthesis is relatively rare. For instance, Brunner and co-workers presented such an an example. They synthesized the A3B porphyrin 133 by mixed condensation of two arylaldehydes and pyrrole,example. withThey onesynthesized of the arylthe A aldehydes3B porphyrin carrying 133 by mixed a PEG condensation chain (n = 2,of 3two or arylaldehydes 17) (Scheme 36and)[ 140]. pyrrole, with one of the aryl aldehydes carrying a PEG chain (n = 2, 3 or 17) (Scheme 36) [140]. The resulting The resulting A3B PEGylated porphyrins 133a–133c were puriﬁed using ordinary silica gel A3B PEGylated porphyrins 133a–133c were purified using ordinary silica gel chromatography chromatography (CH Cl /MeOH mixtures). The PEGylated porphyrins were also amenable to (CH2Cl2/MeOH mixtures).2 2 The PEGylated porphyrins were also amenable to further modification at furtherthe modiﬁcation malonic ester atfunctional the malonic group ester to ge functionalnerate platinum-porphyrin group to generate conjugates. platinum-porphyrin conjugates.

O(CH2CH2O)nCH3

OHC 1. BF3·Et2O, CH2Cl2 2. triethyl orthoacetate O 3. BF ·Et O O CH3 3 2 N N n 4. p-chloroanil H CH (CH CH O) O O + + 3 2 2 n H N N N CO2Et H EtO2C EtO2C CO2Et OHC O n = 2, 3, 17 133 n = 2, 3, 17

O(CH2CH2O)nCH3

Scheme 36. A3B porphyrin carrying three short PEG chains, as described by the group of Brunner [140]. Scheme 36. A3B porphyrin carrying three short PEG chains, as described by the group of Brunner [140]. Another example for the early introduction of PEGylated building blocks was reported by the Anothergroup of Anderson example [70]. for theUsing early a PEGylated introduction benzaldehyde, of PEGylated porphyrin building 26 bearing blocks two was methyl-capped reported by the grouptetraethylene of Anderson glycol [70]. (TEG) Using groups a PEGylated on opposite benzaldehyde, meso-phenylgroups porphyrin was 26prepared.bearing Leaving two methyl-capped the PEG tetraethylenechains intact, glycol it was (TEG) converted groups to th one bis-acetylene opposite meso linked-phenylgroups porphyrin dimer was 134 prepared.. Porphyrin Leaving dimer the134 PEG chainswas intact, found it not was to convertedbe sufficiently to thesoluble bis-acetylene in aqueous linkedmedia for porphyrin biological dimer application.134. Porphyrin Therefore, dimerthese 134 was foundmaterials not were to be further sufﬁciently derivatized soluble with in additional aqueous solubilizing media for biologicalgroups, all application.while the PEG Therefore, functional these materialsgroups were remained further intact derivatized (Scheme 37) with [70]. additional solubilizing groups, all while the PEG functional Starting from the meso-dibromo dimer 49, cationic (pyridinium; cf. Scheme 13), anionic (sulfonate) groups remained intact (Scheme 37)[70]. and Moleculescarboxlyate 2017, 22(cf., 980 Scheme 25) groups were introduced using either Suzuki or Sonogashira27 coupling of 46 strategies. The Senge arylation method was also used to introduce ammonium and pyridyl solubilizing groups (cf. Scheme 7). The dimers were separated by either recrystallization (DMF, Et2O) or by semi-preparative reverse phase HPLC. Due to insufficient solubility of the compounds in regular reverse-phase HPLC solvents (such as CH3CN, MeOH, water), DMF, DMSO, or THF were used. Also due to solubility issues, the authors could not measure logP values for these compounds in octanol:water. However, they did compare the relative polarity of some derivatives by means of their retention times under reverse-phase HPLC conditions (Table 1).

Scheme 37. Hydrophilic bis-acetylene linked porphyrin dimers carrying PEG chains and various other Scheme 37. Hydrophilic bis-acetylene linked porphyrin dimers carrying PEG chains and various other solubilizing motifs, as described by the group of Anderson [70]. solubilizing motifs, as described by the group of Anderson [70]. PEG-substituted dipyrromethanes also found use in the early introduction of solubilizing groups. The group of Lindsey was able to synthesize chlorins from a PEGylated dipyrromethane precursor (Scheme 38) [136]. This strategy also incorporated a bioconjugatable tether at another meso-position, the precursor of which was also introduced at the dipyrromethane stage.

t O CO2 Bu

1. EtMgBr, THF O

(CH2CH2O)4CH3 (CH2CH2O)4CH3 t O O 2. BuO2C S O HN , HN THF, -78 °C N O O (CH CH O) CH (CH CH O) CH HN 2 2 4 3 HN 2 2 4 3 O O (CH2CH2O)4CH3 (CH2CH2O)4CH3

137 138

1. NBS, THF, -78 °C 2. NaBH4, THF/ MeOH, r.t. t O CO2 Bu O CO2H 3. CH3 H3C

N HN , (CH CH O) CH (CH CH O) CH TFA, CH3CN, r.t. 2 2 4 3 2 2 4 3 4. AgOTf, Zn(OAc) , TMPi, O O 2 N N N N CH3CN, ∆, air TFA, CH2Cl2 Zn O H O (CH CH O) CH H (CH CH O) CH N N 2 2 4 3 N N 2 2 4 3 H3C O H3C O (CH2CH2O)4CH3 (CH2CH2O)4CH3 H3C H3C 139 140 Scheme 38. PEGylated synthetic chlorins using PEGylated building blocks, as described by the group of Lindsey [136]. TMPi = 2,2,6,6-tetramethylpiperidine.

Molecules 2017, 22, 980 27 of 46

Molecules 2017, 22, 980 27 of 47

Starting from the meso-dibromo dimer 49, cationic (pyridinium; cf. Scheme 13), anionic (sulfonate) and carboxlyate (cf. Scheme 25) groups were introduced using either Suzuki or Sonogashira coupling strategies. The Senge arylation method was also used to introduce ammonium and pyridyl solubilizing groups (cf. Scheme7). The dimers were separated by either recrystallization (DMF, Et 2O) or by semi-preparative reverse phase HPLC. Due to insufﬁcient solubility of the compounds in regular reverse-phase HPLC solvents (such as CH3CN, MeOH, water), DMF, DMSO, or THF were used. Also due to solubility issues, the authors could not measure logP values for these compounds in octanol:water. However, they did compare the relative polarity of some derivatives by means of their retention times under reverse-phase HPLC conditions (Table1).

Table 1. Comparison of the retention times of hydrophilic porphyrin dimers shown in Scheme 37[ 70].

Porphyrin Dimer Retention Time/min a 51 6.2 29 6.8 135 7.6 136 15.6 88 18.0 a HPLC Conditions: C8 column (5 µm, 3.9 mm × 150 mm), 1 mL/min ﬂow rate; solvent A: 1% aqueous acetic acid; solventScheme B: THF, 37. linear Hydrophilic gradient. bis-acetylene linked porphyrin dimers carrying PEG chains and various other solubilizing motifs, as described by the group of Anderson [70]. PEG-substituted dipyrromethanes also found use in the early introduction of solubilizing groups. The groupPEG-substituted of Lindsey was dipyrromethanes able to synthesize also chlorinsfound use from in the a PEGylated early introduction dipyrromethane of solubilizing precursor groups. The group of Lindsey was able to synthesize chlorins from a PEGylated dipyrromethane (Scheme 38)[136]. This strategy also incorporated a bioconjugatable tether at another meso-position, precursor (Scheme 38) [136]. This strategy also incorporated a bioconjugatable tether at another the precursormeso-position, of which the precursor was also of introduced which was also at the introduced dipyrromethane at the dipyrromethane stage. stage.

t O CO2 Bu

1. EtMgBr, THF O

(CH2CH2O)4CH3 (CH2CH2O)4CH3 t O O 2. BuO2C S O HN , HN THF, -78 °C N O O (CH CH O) CH (CH CH O) CH HN 2 2 4 3 HN 2 2 4 3 O O (CH2CH2O)4CH3 (CH2CH2O)4CH3

137 138

1. NBS, THF, -78 °C 2. NaBH4, THF/ MeOH, r.t. t O CO2 Bu O CO2H 3. CH3 H3C

SchemeScheme 38. PEGylated 38. PEGylated synthetic synthetic chlorins chlorins using using PEGylated building building blocks, blocks, as described as described by the by group the group of Lindsey [136]. TMPi = 2,2,6,6-tetramethylpiperidine. of Lindsey [136]. TMPi = 2,2,6,6-tetramethylpiperidine.

4.1.2. PEGylation of meso-aryl Porphyrins

A number of meso-tetraarylporphyrins bearing PEG groups have been synthesized by PEGylation of porphyrins incorporating suitable linker functionalities on the aryl groups. These porphyrins are usually prepared via Adler or Lindsey methods and the PEG groups can be linked by various methods including etheriﬁcation, amidation or esteriﬁcation reactions. Particularly popular linking groups for the PEGylation of porphyrins are meso-phenol substituents. PEGylation of various Molecules 2017, 22, 980 28 of 46

Table 1. Comparison of the retention times of hydrophilic porphyrin dimers shown in Scheme 37 [70].

Porphyrin Dimer Retention Time/min a 51 6.2 29 6.8 135 7.6 136 15.6 88 18.0

a HPLC Conditions: C8 column (5 μm, 3.9 mm × 150 mm), 1 mL/min flow rate; solvent A: 1% aqueous acetic acid; solvent B: THF, linear gradient.

4.1.2. PEGylation of meso-aryl Porphyrins A number of meso-tetraarylporphyrins bearing PEG groups have been synthesized by PEGylation of porphyrins incorporating suitable linker functionalities on the aryl groups. These porphyrins are Molecules 2017, 22, 980 28 of 47 usually prepared via Adler or Lindsey methods and the PEG groups can be linked by various methods including etherification, amidation or esterification reactions. Particularly popular linking meso-tetrahydroxyphenylgroups for the PEGylation porphyrin of porphyrins derivatives are meso with-phenol a suitably substituents. functionalized PEGylation PEG of various precursor meso yields- water-solubletetrahydroxyphenyl porphyrins, porphyrin with activation derivatives of thewith PEG a suitably group oftenfunctionalized required. PEG precursor yields water-soluble porphyrins, with activation of the PEG group often required. For example, meso-tetrakis(3-hydroxyphenyl)chlorin (141) was rendered water-soluble by For example, meso-tetrakis(3-hydroxyphenyl)chlorin (141) was rendered water-soluble by introducing PEG groups through two different etheriﬁcation strategies. Tetraphenolporphyrin 141 was introducing PEG groups through two different etherification strategies. Tetraphenolporphyrin 141 treatedwas with treatedp-nitrophenylcarbonate- with p-nitrophenylcarbonate- or cyanuric or cyanuric chloride-activated chloride-activated methoxypolyethyleneglycol methoxypolyethyleneglycol to affordto theafford water-soluble the water-soluble PEGylated PEGylated porphyrins porphyrins142 142or or143 143, respectively, respectively (Scheme(Scheme 39)39)[ [141].141 ].

Scheme 39. PEGylated derivatives of meso-tetrakis(3-hydroxyphenyl)chlorin, as described by the Scheme 39. PEGylated derivatives of meso-tetrakis(3-hydroxyphenyl)chlorin, as described by the group group of Sinn [141]. of Sinn [141]. meso-Tetrakis(4-hydroxyphenyl)porphyrin (76) can also be alkylated using various activated PEGs. mesoFor instance,-Tetrakis(4-hydroxyphenyl)porphyrin this procedure has been employed (to76 alkylate) can also 76 by be treatment alkylated with using PEG-mesylates various activated to form PEGs. For instance,144. (Scheme this 40) procedure [137]. has been employed to alkylate 76 by treatment with PEG-mesylates to Under similar conditions, single PEG chains or PEG-dendrimers (Scheme 41) [142] can also be formMolecules144. (Scheme 2017, 22, 980 40 )[137]. 29 of 46 introduced into asymmetric meso-hydroxyphenylporphyrins [143,144]. Vitalini and co-workers

prepared PEGylated derivativesOH of 76 by alkylation of the phenolic oxygensO with a chlorinated PEG [145].

The PEG-functionalized porphyrins could be purified by adding a solution ofO(PEG) thenMe compound in CH2Cl2 to a cold solution of Et2O to induce precipitationOMs (for larger PEGs) [137,143]; porphyrins

bearing smaller PEG-chains could alsoMe(PEG) benO purified by column chromatography (CH2Cl2-acetone- N N , N N MeOH or CH2Cl2/EtOHH mixtures) [137,142]. H O HO OH O H H Cs CO , N N 2 3 N N DMF

144 76

O(PEG) Me O(PEG) Me OH n O n

(PEG)n ~ 750 or 2000 Dalton molecular weight

O(PEG)nMe Scheme 40. PEGylated derivatives of meso-tetra(4-hydroxyphenyl)porphyrin, as described by the Scheme 40. PEGylated derivatives of meso-tetra(4-hydroxyphenyl)porphyrin, as described by the group of Pozzi [137]. group of Pozzi [137].

Under similar conditions, single PEG chains or PEG-dendrimers (Scheme 41)[142] can also be introduced into asymmetric meso-hydroxyphenylporphyrins [143,144]. Vitalini and co-workers prepared PEGylated derivatives of 76 by alkylation of the phenolic oxygens with a chlorinated PEG [145]. The PEG-functionalized porphyrins could be puriﬁed by adding a solution of the compound in CH2Cl2 to a cold solution of Et2O to induce precipitation (for larger PEGs) [137,143]; porphyrins bearing smaller PEG-chains could also be puriﬁed by column chromatography (CH2Cl2-acetone-MeOH or CH2Cl2/EtOH mixtures) [137,142].

Scheme 41. Amphiphilic porphyrin with a PEG-dendrimer, as described by the group of Dumoulin [142].

PEGylation of meso-arylporphyrins was also achieved by inversion of the Williamson ether synthesis reaction partners, i.e., involving a halogenated porphyrin precursor and PEGs bearing a free alcohol. An example is the PEGylation of tetra(p-bromomethylphenyl)porphyrin (147) with a methyl-capped PEG alcohol (Mn = 550) that afforded the tetra-PEGylated porphyrin 148 as the main product, along with partially PEGylated porphyrins (Scheme 42). The porphyrin starting material was prepared by Lindsey porphyrin synthesis from 4-(bromomethyl)benzaldehyde and pyrrole [146]. The PEGylated products were amenable to aqueous work-up (extraction with CH2Cl2) and were purified by HPLC.

Scheme 42. PEGylated meso-aryl porphyrins by benzylation of a PEG with tetra(p-bromomethylphenyl) porphyrin, as described by the group of Lee [146].

Molecules 2017, 22, 980 29 of 46

OH O

Molecules 2017, 22, 980 O(PEG)nMe 29 of 46

OMs

OH O Me(PEG)nO N N , N N O(PEG)nMe H H O HO OH O H H Cs CO , OMs N N 2 3 N N DMF

Me(PEG)nO , N N 144 N N 76 H H O HO OH O H H Cs CO , N N 2 3 N N DMF O(PEG) Me O(PEG) Me OH n O n 144 76 (PEG)n ~ 750 or 2000 Dalton molecular weight

O(PEG) Me O(PEG) Me OH n O n

O(PEG)nMe (PEG)n ~ 750 or 2000 Dalton molecular weight Molecules 2017Scheme, 22, 980 40. PEGylated derivatives of meso-tetra(4-hydroxyphenyl)porphyrin, as described by the 29 of 47 group of Pozzi [137]. O(PEG)nMe Scheme 40. PEGylated derivatives of meso-tetra(4-hydroxyphenyl)porphyrin, as described by the group of Pozzi [137].

SchemeScheme 41. 41. Amphiphilic porphyrin porphyrin with awith PEG-dendrimer, a PEG-dendrimer, as described by as the described group of Dumoulin by the [142]. group of Dumoulin [142]. PEGylation of meso-arylporphyrins was also achieved by inversion of the Williamson ether synthesisScheme reaction 41. Amphiphilic partners, porphyrin i.e., involving with a PEG-dendrimer, a halogenated as porphyrin described by precursor the group ofand Dumoulin PEGs bearing[142]. a PEGylationfree alcohol. An of mesoexample-arylporphyrins is the PEGylation was of also tetra( achievedp-bromomethylphenyl)porphyrin by inversion of the Williamson (147) with a ether PEGylation of meso-arylporphyrins was also achieved by inversion of the Williamson ether synthesismethyl-capped reaction partners,PEG alcohol i.e., (Mn involving = 550) that aafforded halogenated the tetra-PEGylated porphyrin precursorporphyrin 148 and as PEGs the main bearing synthesis reaction partners, i.e., involving a halogenated porphyrin precursor and PEGs bearing a a freeproduct, alcohol. along An examplewith partially is the PEGylated PEGylation porphyrins of tetra( (Schemep-bromomethylphenyl)porphyrin 42). The porphyrin starting material (147) with free alcohol. An example is the PEGylation of tetra(p-bromomethylphenyl)porphyrin (147) with a a methyl-cappedwas prepared PEGby Lindsey alcohol porphyrin (Mn = 550) synthesis that afforded from 4-(bromomethyl)benzaldehyde the tetra-PEGylated porphyrin and pyrrole148 as [146]. the main methyl-capped PEG alcohol (Mn = 550) that afforded the tetra-PEGylated porphyrin 148 as the main product,The alongPEGylated with products partially were PEGylated amenable porphyrins to aqueous (Schemework-up 42(extraction). The porphyrin with CH2Cl starting2) and were material product, along with partially PEGylated porphyrins (Scheme 42). The porphyrin starting material purified by HPLC. was preparedwas prepared by Lindsey by Lindsey porphyrin porphyrin synthesis synthesis fromfrom 4-(bromomethyl)benzaldehyde4-(bromomethyl)benzaldehyde and andpyrrole pyrrole [146]. [ 146]. The PEGylatedThe PEGylated products products were were amenable amenable to to aqueous aqueous work-up (extraction (extraction with with CH CH2Cl22)Cl and2) andwere were puriﬁedpurified by HPLC. by HPLC.

Scheme 42. PEGylated meso-aryl porphyrins by benzylation of a PEG with tetra(p-bromomethylphenyl) porphyrin, as described by the group of Lee [146]. SchemeScheme 42. 42. PEGylatedPEGylated meso-aryl mesoporphyrins-aryl by porphyrins benzylation of a by PEG benzylationwith tetra(p-bromomethylphenyl) of a PEG with tetra(porphyrin,p-bromomethylphenyl)porphyrin, as described by the group of as Lee described [146]. by the group of Lee [146].

meso-Aryl porphyrins bearing peripheral carboxylic acid functional groups can be PEGylated by amide formation using an amine-terminated PEG. For instance, Scolaro and co-workers prepared PEGylated derivatives of meso-tetrakis(4-carboxyphenyl)porphyrin (149) by treatment with Jeffamine M-600 (n = 7–9) (Scheme 43)[147]. Also starting from tetraacid 149, Lovell and co-workers reacted it with a variety of homobi-functional PEG-diamines (average Mw ranging from 150 Da to 10 kDa) to synthesize a PEG-linked porphyrin mesh 151 (Figure9)[ 148]. This reaction illustrates the complex cross-linked structure formed when using PEGs capable of reacting at both ends. The porphyrin-PEG-mesh was puriﬁed by dialysis, followed by addition of citric acid to precipitate unreacted porphyrin. PEGylated porphyrins and hydroporphyrins with amide linkages can also be prepared starting with aminophenyl porphyrins. For instance, Peng et al. functionalized a chlorin with a poly-(ε-caprolactone)-polyethyleneglycol) diblock copolymer [149]. Introduction of the PEG-polymer was achieved by treatment of meso-tetrakis(4-aminophenyl)chlorin with the acid chloride of the diblock copolymer. The polymer-functionalized porphyrin was puriﬁed by precipitation with Et2O, followed by a dialysis step in acetone. Vicente and co-workers prepared water-soluble porphyrin-peptide Molecules 2017, 22, 980 30 of 46

Scheme 43. PEGylated porphyrins derived from meso-tetrakis(4-carboxyphenyl)porphyrin using a PEG-amine, as described by the group of Scolaro [147].

Also starting from tetraacid 149, Lovell and co-workers reacted it with a variety of homobi- functional PEG-diamines (average Mw ranging from 150 Da to 10 kDa) to synthesize a PEG-linked porphyrin mesh 151 (Figure 9) [148]. This reaction illustrates the complex cross-linked structure Scheme 43. PEGylated porphyrins derived from meso-tetrakis(4-carboxyphenyl)porphyrin using a Schemeformed when 43. PEGylated using PEGs porphyrins capable of derivedreacting fromat bothmeso ends.-tetrakis(4-carboxyphenyl)porphyrin The porphyrin-PEG-mesh was purified using PEG-amine, as described by the group of Scolaro [147]. aby PEG-amine, dialysis, followed as described by addition by the of group citric of acid Scolaro to precipitate [147]. unreacted porphyrin. Also starting from tetraacid 149, Lovell and co-workers reacted it with a variety of homobi- functional PEG-diamines (average Mw ranging from 150 Da to 10 kDa) to synthesize a PEG-linked porphyrin mesh 151 (Figure 9) [148]. This reaction illustrates the complex cross-linked structure formed when using PEGs capable of reacting at both ends. The porphyrin-PEG-mesh was purified by dialysis, followed by addition of citric acid to precipitate unreacted porphyrin.

Figure 9. Partial molecular structures of PEG-linked porphyrin mesh 151. Figure 9. Partial molecular structures of PEG-linked porphyrin mesh 151. PEGylated porphyrins and hydroporphyrins with amide linkages can also be prepared starting Thewith amineaminophenyl functionality porphyrins. in 152 Forwas instance, reacted withPeng diglycolic et al. functionalized anhydride, a followed chlorin with by amide-coupling a poly-(ε- usingcaprolactone)-polyethyleneglycol) a PEG-amine and Boc-deprotection diblock copolymer (Scheme 44[149].). A Introd peptidyluction resinof the can PEG-polymer be coupled was to the hydroxybenzotriazole Figure (HOBt) 9. Partial ester molecular of the porphyrin structures of154 PEG-linked[150]. porphyrin More hydrophilic mesh 151. PEGylated A3B porphyrins bearing three carboxyphenyl groups were also prepared in a similar manner [150]. Oligo-ethylenePEGylated glycol porphyrins amide-linkages and hydroporphyrins have also beenwith amide utilized linkages as hydrophilic can also be prepared spacers instarting instances that requirewith aminophenyl designed structuresporphyrins. onFor the instance, periphery Peng of et aal. hydrophilic functionalized porphyrin. a chlorin Usingwith a thispoly-( strategy,ε- Alessiocaprolactone)-polyethyleneglycol) and co-workers have prepared diblock ruthenium-porphyrin copolymer [149]. Introd conjugatesuction of withthe PEG-polymer oligoethylene was glycol spacers [151]. This methodology has also been used to develop Rhenium (I)-porphyrin conjugates in a similar manner [152]. Molecules 2017, 22, 980 31 of 46

achieved by treatment of meso-tetrakis(4-aminophenyl)chlorin with the acid chloride of the diblock copolymer. The polymer-functionalized porphyrin was purified by precipitation with Et2O, followed by a dialysis step in acetone. Vicente and co-workers prepared water-soluble porphyrin-peptide conjugates with a PEG linker on one meso-aryl group starting from an AB3 porphyrin 152 bearing one Molecules 2017, 22, 980 31 of 46 p-aminophenyl group. The amine functionality in 152 was reacted with diglycolic anhydride, followed by amide- achieved by treatment of meso-tetrakis(4-aminophenyl)chlorin with the acid chloride of the diblock coupling using a PEG-amine and Boc-deprotection (Scheme 44). A peptidyl resin can be coupled to copolymer. The polymer-functionalized porphyrin was purified by precipitation with Et2O, followed the hydroxybenzotriazole (HOBt) ester of the porphyrin 154 [150]. More hydrophilic PEGylated A3B by a dialysis step in acetone. Vicente and co-workers prepared water-soluble porphyrin-peptide porphyrins bearing three carboxyphenyl groups were also prepared in a similar manner [150]. Oligo- conjugates with a PEG linker on one meso-aryl group starting from an AB3 porphyrin 152 bearing one pethylene-aminophenyl glycol group. amide-linkages have also been utilized as hydrophilic spacers in instances that requireThe designed amine functionality structures on in the 152 periphery was reacted of a hydrophilic with diglycolic porphyrin. anhydride, Using followedthis strategy, by amide-Alessio and co-workers have prepared ruthenium-porphyrin conjugates with oligoethylene glycol spacers [151]. coupling using a PEG-amine and Boc-deprotection (Scheme 44). A peptidyl resin can be coupled to This methodology has also been used to develop Rhenium (I)-porphyrin conjugates in a similar the hydroxybenzotriazole (HOBt) ester of the porphyrin 154 [150]. More hydrophilic PEGylated A3B manner [152]. porphyrins bearing three carboxyphenyl groups were also prepared in a similar manner [150]. Oligo- Lastly, PEGylation of meso-hydroxyphenylporphyrins can be achieved utilizing ester linkages. ethylene glycol amide-linkages have also been utilized as hydrophilic spacers in instances that MoleculesThus,2017 Diederich, 22, 980 and co-workers prepared dendritic porphyrin 156 by esterification of porphyrin tetraol31 of 47 require designed structures on the periphery of a hydrophilic porphyrin. Using this strategy, Alessio 155 with a carboxylic acid-functionalized dendron under Mitsunobu conditions (Scheme 45) [153]. and co-workers have prepared ruthenium-porphyrin conjugates with oligoethylene glycol spacers [151].

This methodology hasPh also been usedO toO developO RheniumPh (I)-porphyrin conjugates in a similar manner [152]. O O N N N N Lastly, PEGylationH of meso-hydroxyphenylporphyrinsDMF, r.t. H can be achievedO utilizingCO2H ester linkages. Ph NH2 Ph N H H H Thus, Diederich andN co-workersN prepared dendritic porphyrinN N 156 by esterification of porphyrin tetraol 155 with a carboxylic acid-functionalized dendron under Mitsunobu conditions (Scheme 45) [153]. Ph 152 Ph 153

Ph O O O Ph 1. HOBt/TBTU/DIEA, t O NH2CHO2CH2(OCH2CH2)5OCH2CO2 Bu N N N N 2. TFA H DMF, r.t. H O CO2H Ph NH2 Ph N H Ph H H N N N N O O N N Ph 152 H Ph 153 O O Ph N N O CO2H H H H N N 5 1. HOBt/TBTU/DIEA, NH CH CH (OCH CH ) OCH CO tBu Ph 154 2 2 2 2 2 5 2 2 2. TFA Ph Scheme 44. PEGylated AB3 porphyrin with carboxylic acid bioconjugation handle, as described by Scheme 44. PEGylated AB3 porphyrin with carboxylic acid bioconjugation handle, as described by O O the group of Vicente [150]. HOBt = 1-hydroxybenzotriazole,N N TBTU = O-(benzotriazol1-yl)N,N,N′,N′- 0 0 the group of Vicente [150]. HOBt = 1-hydroxybenzotriazole,H TBTUO = O-(benzotriazol1-yl)O N,N,N ,N - Ph N N O CO2H tetramethyluronium tetrafluoroborate, DIEA = NH,N-diisopropylethylamine.H H tetramethyluronium tetrafluoroborate, DIEA = NN,N-diisopropylethylamine.N 5

Ph 154 Lastly, PEGylation of meso-hydroxyphenylporphyrins can be achieved utilizing ester linkages. Scheme 44. PEGylated AB3 porphyrin with carboxylic acid bioconjugation handle, as described by 156 Thus, Diederichthe group and of Vicente co-workers [150]. HOBt prepared = 1-hydroxybenzotriazole, dendritic porphyrin TBTU =by O-(benzotriazol1-yl) esteriﬁcation ofN porphyrin,N,N′,N′- tetraol 155 withtetramethyluronium a carboxylic acid-functionalized tetrafluoroborate, DIEA dendron = N,N under-diisopropylethylamine. Mitsunobu conditions (Scheme 45)[153].

Scheme 45. Porphyrin-PEG dendrimer conjugates, as described by the group of Diederich [153]. TMAD = N,N,N′,N′-tetramethylazodicarboxamide.

The extension of the reactive alcohol site from the phenolic position using an alkyl chain was employed to accommodate the bulky PEG-dendrimer substituents. The resulting porphyrin-dendrimers were purified by preparative gel permeation chromatography and were soluble in phosphate buffer Scheme 45. Porphyrin-PEG dendrimer conjugates, as described by the group of Diederich [153]. Scheme 45. Porphyrin-PEG dendrimer conjugates, as described by the group of Diederich [153]. TMAD = N,N,N′,N′-tetramethylazodicarboxamide. TMAD = N,N,N0,N0-tetramethylazodicarboxamide. The extension of the reactive alcohol site from the phenolic position using an alkyl chain was employedThe extension to accommodate of the the reactive bulky PEG-dendrimer alcohol site substituents. from the The phenolic resulting position porphyrin-dendrimers using an alkyl chainwere was purified employed by preparative to accommodate gel permeation the chro bulkymatography PEG-dendrimer and were soluble substituents. in phosphate The buffer resulting porphyrin-dendrimers were puriﬁed by preparative gel permeation chromatography and were soluble in phosphate buffer at pH 7. Alternatively, the PEGylation of a meso-hydroxphenyl A2B2 porphyrin by DCC/DMAP-mediated esteriﬁcation with a PEG-carboxylic acid (1000 Da) was reported (Scheme 46)[154]. π-Extended porphyrin derivatives may also be subjected to the same PEGylation strategies as seen for regular porphyrins. For instance, PEGylation of the phenolic oxygens in quinoline-annulated porphyrin 160 was reported by Luciano et al. (Scheme 47)[14] using a similar O-alkylation method as described for regular porphyrins (Scheme 40). Precursor porphyrin 159 was prepared from meso-tetrakis(4-methoxyphenyl)porphyrin. A BBr3-mediated deprotection was employed to deprotect the phenolic oxygens as the penultimate step of the synthesis. The phenol could then be PEGylated using either a short (n = 4) or long chain (avg. MW 550, n ≈ 12) PEG-mesylate [14]. The short PEG chain derivative 161a was found to be only slightly soluble in water. However, the derivative bearing long PEGs (161b) was soluble in PBS to Molecules 2017, 22, 980 32 of 46

at pH 7. Alternatively, the PEGylation of a meso-hydroxphenyl A2B2 porphyrin by DCC/DMAP-mediated Moleculesesterification2017, 22, 980 with a PEG-carboxylic acid (1000 Da) was reported (Scheme 46) [154]. 32 of 47

Molecules 2017, 22, 980 32 of 46 OH OCO2(CH2CH2O)nCH3 form ~30 mM solutions and were used as photoacoustic imaging contrast agents for in vivo imaging at pH 7. Alternatively, the PEGylation of a meso-hydroxphenyl A2B2 porphyrin by DCC/DMAP-mediated of tumorsesterification in a mouse with a model PEG-carboxylic [14]. acid (1000 Da) was reported (Scheme 46) [154]. CH3(OCH2CH2)nCO2H, N N N DCC, DMAP N H H OH Ph OCO2(CH2CHPh2O)nCH3 Ph H Ph H N N N N

157 158 CH3(OCH2CH2)nCO2H, N N N DCC, DMAP N H Ph H Ph Ph OHH Ph OCOH 2(CH2CH2O)nCH3 N N N N

Scheme 46. PEGylated A2B2 porphyrin, as described by the group of Nawaz [154]. DCC = dicyclohexylcarbodiimide, DMAP = 4-dimethylaminopyridine.157 158

π-Extended porphyrin derivativesOH may also be subjected to OCOthe2 (CHsame2CH2O) PEGylationnCH3 strategies as

seen Schemefor regular 46. PEGylatedporphyrins. A 2ForB2 porphyrin, instance, PEGylationas described ofby thethe phenolicgroup of oxygensNawaz [154]. in quinoline-annulated DCC = dicyclo- Scheme 46. PEGylated A2B2 porphyrin, as described by the group of Nawaz [154]. DCC = porphyrinhexylcarbodiimide, 160 was reported DMAP by = 4-dimethylaminopyridine. Luciano et al. (Scheme 47) [14] using a similar O-alkylation method dicyclo-hexylcarbodiimide, DMAP = 4-dimethylaminopyridine. as described for regular porphyrins (Scheme 40). π-Extended porphyrin derivatives may also be subjected to the same PEGylation strategies as seen for regular porphyrins. For instance, PEGylation of the phenolic oxygens in quinoline-annulated porphyrin 160 was reported by Luciano et al. (Scheme 47) [14] using a similar O-alkylation method as described for regular porphyrins (Scheme 40).

SchemeScheme 47. PEGylated47. PEGylated quinoline-annulated quinoline-annulated porphyrins,porphyrins, as as described described by bythe the group group of Brückner of Brückner [14]. [14].

Precursor porphyrin 159 was prepared from meso-tetrakis(4-methoxyphenyl)porphyrin. A BBr3- Brücknermediated deprotection and co-workers was employed were able to deprotect to take the advantage phenolic oxygens of the well-knownas the penultimate SNAr step reactivity of of mesothe-pentafluorophenylporphyrins synthesis.Scheme 47. The PEGylated phenol couldquinoline-annulated then be toward PEGylated porphyrins, nucleophiles using as either described ata short the by p(then-F = group 4) positions or longof Brückner chain to introduce (avg. [14]. MW PEG groups550, to n pyrrole-modified≈ 12) PEG-mesylate porphyrins[14]. The short (PMPs) PEG chain ata derivative late stage 161a of was the found synthetic to be sequence only slightly toward meso-arylmetalloporpholactonessolublePrecursor in water. porphyrin However, 159 the wasderivative [138 prepared,139 bearing,155 from] (Schemelong meso PEGs-tetrakis(4-methoxyphenyl)porphyrin. (48161b).) was This soluble allowed in PBS the to form preparation ~30A BBr mM3- of a varietymediatedsolutions of PEGylated anddeprotection were used porpholactone was as photoacousticemployed to metal deprotectimaging complexes cont the rastphenolic agents (163M oxygens for) thatin vivo as were the imaging penultimate used of astumors optical step in of a high pH orthemousecyanide synthesis. model sensors The[14]. phenol in could water then [139 be]. PEGylated The PEGylated using either derivatives a short (n = 4) were or long purified chain (avg. by silicaMW gel 550, nBrückner ≈ 12) PEG-mesylate and co-workers [14]. were The able short to PEGtake advantagechain derivative of the well-known161a was found SNAr to reactivity be only ofslightly meso- chromatography (CH2Cl2/5% MeOH). Similarly, thiol-functionalized sugars were introduced into solublepentafluorophenylporphyrins in water. However, the derivativetoward nucleophiles bearing long at PEGs the p (-F161b positions) was soluble to introduce in PBS to PEG form groups ~30 mM to meso-pentafluorophenylporphyrins using the S Ar reaction, also resulting in their solubilization in solutionspyrrole-modified and were porphyrins used as photoacoustic (PMPs) at aimaging lateN stage cont ofrast the agents synthetic for in sequence vivo imaging toward of tumors meso-aryl- in a aqueousmousemetalloporpholactones solutions model [14]. [156 ]. [138,139,155] (Scheme 48). This allowed the preparation of a variety of BuildingPEGylatedBrückner onporpholacton and previous co-workerse metal efforts were complexes for able the to ( 163M solubilizationtake advantage) that were of used of the antimony aswell-known optical high porphyrins S NpHAr orreactivity cyanide by axialof sensors meso ligand- exchangepentafluorophenylporphyrins with alcohols (cf. Scheme toward 11 nucleophiles), Yasuda and at the co-workers p-F positions prepared to introduce hydrophilic PEG groups PEGylated to phosphoruspyrrole-modified porphyrins, porphyrins such as (PMPs) tetraphenylporphyrin at a late stage ofderivative the synthetic164 sequence(Figure 10toward) by introduction meso-aryl- of shortmetalloporpholactones PEGs as axial ligands. [138,139,155 Incorporation] (Scheme of the axial-PEGs48). This allowed furnished the highlypreparation water-soluble of a variety derivatives. of PorphyrinPEGylated164 ,porpholacton for example,e metal has a complexes water-solubility (163M) that of 17.3were mMused [as90 optical]. high pH or cyanide sensors

Molecules 2017, 22, 980 33 of 46

in water [139]. The PEGylated derivatives were purified by silica gel chromatography (CH2Cl2/5% MeOH). Similarly, thiol-functionalized sugars were introduced into meso-pentafluorophenylporphyrins using the SNAr reaction, also resulting in their solubilization in aqueous solutions [156].

Molecules 2017, 22, 980 33 of 46

in water [139]. The PEGylated derivatives were purified by silica gel chromatography (CH2Cl2/5% MoleculesMeOH).2017, 22 Similarly,, 980 thiol-functionalized sugars were introduced into meso-pentafluorophenylporphyrins33 of 47 using the SNAr reaction, also resulting in their solubilization in aqueous solutions [156].

Scheme 48. PEGylated porpholactone derived from meso-tetrakis(pentafluorophenyl)porphyrin derivatives, as described by the group of Brückner [139].

Building on previous efforts for the solubilization of antimony porphyrins by axial ligand exchange with alcohols (cf. Scheme 11), Yasuda and co-workers prepared hydrophilic PEGylated phosphorusScheme 48.porphyrins, PEGylated porpholactonesuch as tetraphenylporphyrin derived from meso-tetrakis(pentafluorophenyl)porphyrin derivative 164 (Figure 10) by introduction derivatives, of Scheme 48. PEGylated porpholactone derived from meso-tetrakis(pentaﬂuorophenyl)porphyrin shortas PEGs described as byaxial the groupligands. of BrücknerIncorporation [139]. of the axial-PEGs furnished highly water-soluble derivatives,derivatives. asPorphyrin described 164 by, for the example, group of Brücknerhas a water-solubility [139]. of 17.3 mM [90]. Building on previous efforts for the solubilization of antimony porphyrins by axial ligand exchange with alcohols (cf. Scheme 11), Yasuda and co-workers prepared hydrophilic PEGylated phosphorus porphyrins, such as tetraphenylporphyrin derivative 164 (Figure 10) by introduction of short PEGs as axial ligands. Incorporation of the axial-PEGs furnished highly water-soluble derivatives. Porphyrin 164, for example, has a water-solubility of 17.3 mM [90].

Figure 10. Molecular structure of axially-PEGylated phosphorus porphyrin 164. Figure 10. Molecular structure of axially-PEGylated phosphorus porphyrin 164. 4.1.3. Porphyrins PEGylated at Their β-Positions 4.1.3. Porphyrins PEGylated at Their β-Positions A number of PEGylated β-alkyl-porphyrins and -chlorins were prepared. Representative of Athese number are a number of PEGylated of PEGylatedβ-alkyl-porphyrins chlorin e6 derivative ands, -chlorinsprepared firstly were by prepared. Hamblin et Representative al. [157]. The of thesePEGylation are a number increasedFigure of PEGylated10. tumor Molecular targeting chlorinstructure of theof e6 axially-P photosensitizer. derivatives,EGylated prepared phosphorus Mono-(165a ﬁrstly porphyrin), di-( by165b Hamblin164),. and tri-( et165c al.) [ 157]. The PEGylationPEGylated derivatives increased tumorof chlorin targeting e6 were ofalso the prepared photosensitizer. in which the Mono-( PEG groups165a), di-(were165b introduced), and tri-( by 165c) 4.1.3. Porphyrins PEGylated at Their β-Positions PEGylatedesterification derivatives at one to of three chlorin of its e6 carboxylic were also ac preparedids using a in short which methyl-capped the PEG groups PEG (Scheme were introduced 49) [158]. by Longer reaction times were needed to increase the yield of the tri-PEGylated product 165c. The esteriﬁcationA number at one toof threePEGylated of its carboxylicβ-alkyl-porphyrins acids using and a-chlorins short methyl-capped were prepared. PEG Representative (Scheme 49 of)[ 158]. authors also measured the solubility of the compounds to be 1.8 ± 1.3 mM for 11, 2.3 ± 1.0 mM for Longerthese reaction are a number times were of PEGylated neededto chlorin increase e6 derivative the yields, of prepared the tri-PEGylated firstly by Hamblin product et165c al. [157].. The The authors 165aPEGylation, 3.3 ± 0.9increased mM for tumor 165b ,targeting and 3.9 ±of 0.8 the mM photosensitizer. for 165c in 1%Mono-( (v/v)165a DMSO/water,), di-(165b), indicating and tri-(165c the) also measured the solubility of the compounds to be 1.8 ± 1.3 mM for 11, 2.3 ± 1.0 mM for 165a, increasedPEGylated aqueous derivatives solubility of chlorin with e6 the were increa alsose prepared of the number in which of PEG the PEG chains. groups Products were 165aintroduced and 165b by ± ± 3.3 areesterification0.9 single mM forisomers, at165b one , indicatingto and three 3.9 of aits 0.8sterics-controlle carboxylic mM for ac165cidsd usingregioselectivityin 1% a (shortv/v) methyl-capped DMSO/water, of the sequential PEG indicating PEGylation.(Scheme the49) [158]. increased aqueousLonger solubilityThe reaction propionic with times side the were chains increase needed in protoporphyrin of theto incr numberease the166 of yield PEGcould chains.of also the be tri-PEGylated Productsfunctionalized165a product withand PEG-chains165b 165care. The single isomers,through indicating amide alinkages, sterics-controlled whereby a regioselectivityshort diamine established of the sequential the requisite PEGylation. amine linkage sites. Moleculesauthors 2017also, 22 measured, 980 the solubility of the compounds to be 1.8 ± 1.3 mM for 11, 2.3 ± 1.0 mM34 of for 46 Amine165a, 3.3 intermediate ± 0.9 mM for167 165b was, andthen 3.9reacted ± 0.8 withmM forsuccinimidyl-PEG 165c in 1% (v/5000v) DMSO/water,to afford the indicatingwater-soluble the PEGylatedincreased aqueous protoporphyrin solubility derivative with the increa168 (Schemese of the 50), number and its of zinc PEG complex chains. Products[159,160]. 165a and 165b are singleOther isomers, PEGylated indicating porphyrins a sterics-controlle were preparedd regioselectivity using ether linkages. of the sequential For example, PEGylation. brominated hematoporphyrinThe propionic derivative side chains 169 inwas protoporphyrin converted to the 166 corres couldponding also be PEGylated functionalized compounds with PEG-chains 170a–170f bythrough treatment amide with linkages, a stoichiometric whereby excess a short of a mediaminethyl-capped established PEG (Scheme the requisite 51) [161,162]. amine Concomitantly, linkage sites. theAmine propionic intermediate acid side 167 chainswas then were reacted also derivawith succinimidyl-PEGtized with PEG chains.5000 to affordAfter hydrolysisthe water-soluble of the propionicPEGylated ester protoporphyrin side chains, derivative platinum-conjugates 168 (Scheme were 50), andprepared its zinc and complex evaluated [159,160]. for their antitumor phototoxictyOther PEGylated and cytotoxicity porphyrins [161,162]. were The prepared PEGylated using derivatives ether linkages. were amenable For example, to aqueous brominated work- uphematoporphyrin and purified by derivative alumina 169chromatography. was converted to the corresponding PEGylated compounds 170a–170f by treatment with a stoichiometric excess of a methyl-capped PEG (Scheme 51) [161,162]. Concomitantly, the propionic acid side chains were also derivatized with PEG chains. After hydrolysis of the propionic ester side chains, platinum-conjugates were prepared and evaluated for their antitumor phototoxicty and cytotoxicity [161,162]. The PEGylated derivatives were amenable to aqueous work- up and purified by alumina chromatography.

SchemeScheme 49. 49.PEGylated PEGylated derivatives derivatives of ofchlorin chlorin e6, as e6, described as described by the group by theof Greer group [158]. of EDC Greer = 1- [158]. ethyl3-(3-dimethylaminopropyl)carbodiimide, DMAP = 4-dimethylaminopyridine. EDC = 1-ethyl3-(3-dimethylaminopropyl)carbodiimide, DMAP = 4-dimethylaminopyridine.

The propionic side chains in protoporphyrin 166 could also be functionalized with PEG-chains through amide linkages, whereby a short diamine established the requisite amine linkage sites. Amine intermediate 167 was then reacted with succinimidyl-PEG5000 to afford the water-soluble PEGylated protoporphyrin derivative 168 (Scheme 50), and its zinc complex [159,160].

Scheme 50. PEGylated protoporphyrin and its zinc complex, as described by the group of Maeda [159].

Br O(CH2CH2O)nCH3 H3C CH3 H3C CH3 CH3 CH3 H3C H3C N N Br N N O(CH2CH2O)nCH3 H H H excess ROH H N N N N

H3C CH3 H3C CH3

MeO2C CO2Me H3Cn(OH2CH2C)O2C CO2(CH2CH2O)nCH3 169 170: n = 2, 3, 4, 5, 12, 17 Scheme 51. PEGylated hematoporphyrin, as described by Brunner and Sohn [161,162].

Etherification conditions were also applied to cycloimide-bacteriochlorin alcohol derivative 171 (Scheme 52) [163]. Activation of the hydroxyethyl substituent on the bacteriochlorin 171 with trifluoroacetic anhydride, followed by treatment with hydroxyl-terminated short PEGs and diols of varying length gave the corresponding derivatives 172a–172d. The products were insoluble in water, but aqueous solutions were prepared with the help of 10% Cremophore EL®, a PEGylated castor oil formulation vehicle.

Molecules 2017, 22, 980 34 of 46

Molecules 2017Scheme, 22, 980 49. PEGylated derivatives of chlorin e6, as described by the group of Greer [158]. EDC = 1- 34 of 47 ethyl3-(3-dimethylaminopropyl)carbodiimide, DMAP = 4-dimethylaminopyridine.

Scheme 49. PEGylated derivatives of chlorin e6, as described by the group of Greer [158]. EDC = 1- ethyl3-(3-dimethylaminopropyl)carbodiimide, DMAP = 4-dimethylaminopyridine.

Scheme 50. PEGylated protoporphyrin and its zinc complex, as described by the group of Maeda [159]. Scheme 50. PEGylated protoporphyrin and its zinc complex, as described by the group of Maeda [159].

Br O(CH2CH2O)nCH3 H3C CH3 H3C CH3 Other PEGylated porphyrins wereCH3 prepared using ether linkages.CH3 For example, brominated H3C H3C N N Br N N O(CH2CH2O)nCH3 hematoporphyrin derivative 169H was converted to the correspondingH PEGylated compounds H excess ROH H 170a–170f by treatment withN a stoichiometricN excess of a methyl-cappedN N PEG (Scheme 51)[161,162]. H C CH H C CH Concomitantly, the propionic3 acid side chains3 were also3 derivatized with3 PEG chains. After hydrolysis of the propionic ester side chains, platinum-conjugates were prepared and evaluated for their antitumor MeO2C CO2Me H3Cn(OH2CH2C)O2C CO2(CH2CH2O)nCH3 phototoxicty and cytotoxicity [161169,162]. The PEGylated derivatives 170: n = 2, 3, 4, 5, were12, 17 amenable to aqueous work-up and puriﬁedScheme byScheme 50. alumina PEGylated 51. PEGylated chromatography. protoporphyrin hematoporphyrin, and its zinc complex,as described as described by Brunner by the and group Sohn of [161,162]. Maeda [159].

Br O(CH2CH2O)nCH3 H3C Etherification conditions wereCH3 also applied to cycloimide-bacteriochlorinH3C CH3 alcohol derivative 171 CH3 CH3 (Scheme 52) [163]. HActivation3C of the hydroxyethylH3 Csubstituent on the bacteriochlorin 171 with N N Br N N O(CH2CH2O)nCH3 trifluoroacetic anhydride, followedH by treatment with hydroxyl-terminatedH short PEGs and diols of H excess ROH H varying length gave the correspondingN N derivatives 172a–172dN . TheN products were insoluble in water, CH CH but aqueous solutionsH3C were prepared3 with the help ofH3C 10% Cremophore3 EL®, a PEGylated castor oil formulation vehicle. MeO2C CO2Me H3Cn(OH2CH2C)O2C CO2(CH2CH2O)nCH3 169 170: n = 2, 3, 4, 5, 12, 17 SchemeScheme 51. 51.PEGylated PEGylated hematoporphyrin, hematoporphyrin, as descr describedibed by by Brunner Brunner and and Sohn Sohn [161,162]. [161,162 ].

Etherification conditions were also applied to cycloimide-bacteriochlorin alcohol derivative 171 Etheriﬁcation(Scheme 52) [163]. conditions Activation were of the also hydrox appliedyethyl to cycloimide-bacteriochlorinsubstituent on the bacteriochlorin alcohol 171 derivativewith 171 (Schemetrifluoroacetic 52)[ 163anhydride,]. Activation followed of by the treatment hydroxyethyl with hydroxyl-terminated substituent on the short bacteriochlorin PEGs and diols171 of with triﬂuoroaceticvarying length anhydride, gave the followedcorresponding by treatment derivatives with 172a hydroxyl-terminated–172d. The products were short insoluble PEGs in and water, diols of varyingbut lengthaqueous gave solutions the corresponding were prepared with derivatives the help172a of 10%–172d Cremophore. The products EL®, a PEGylated were insoluble castor in oil water, but aqueousformulation solutions vehicle. were prepared with the help of 10% Cremophore EL®, a PEGylated castor oil formulationMolecules 2017 vehicle., 22, 980 35 of 46

OR OH H3C H3C O O CH3 CH3 F C O CF 1. 3 3 H3C 172a: R = OH H3C O CH N N CH3 N N 3 2. HO-R H H H 172b: R = O H O OH N N N N H3C OH H3C 172c: R = OH

O N O O N O 172d: R = CO2H OCH3 CO2H OCH3 OCH3 171 172 SchemeScheme 52. Hydrophilic52. Hydrophilic bacteriochlorin bacteriochlorin cycloimides,cycloimides, as as described described by by the the group group of Feofanov of Feofanov [163]. [ 163].

The meso-Suzuki coupling method developed by Lindsey and co-workers and utilized for the introductionThe meso-Suzuki of a variety coupling of solubi methodlization developed groups to hydroporphyrins by Lindsey and (cf. co-workers Schemes 5, and 12 and utilized 26) was for the introductionalso utilized of afor variety the introduction of solubilization of PEG groups groups to tobacteriochlorin hydroporphyrins 173 (Scheme (cf. Schemes53) [164].5 Bacterio-, 12 and 26) waschlorin also utilized 173 was forprepared the introduction by Suzuki coupling of PEG of the groups corresponding to bacteriochlorin meso-bromobacteriochlorin173 (Scheme with53)[ 164]. an aryl-boronic ester bearing two unprotected aldehyde functional groups. The aldehyde functionalities were PEGylated by reductive amination with an amine-terminated PEG to afford the water-soluble PEGylated bacteriochlorin 174.

Scheme 53. PEGylated bacteriochlorins formed by reductive amination, as described by the group of Lindsey [164].

Another representative example for the introduction of PEG groups via Suzuki coupling of dibromobacteriochlorin 19 with a Boc-protected amine-derivatized boronic ester, followed by Boc- deprotection under standard conditions, afforded diaryl bacteriochlorin 175 carrying two amine groups. The amines were PEGylated by amide formation with a PEG-NHS ester to afford bacteriochlorin 176 (Scheme 54) [135]. Derivatives bearing bioconjugatable tethers (177) and (178) were also prepared using a regioselective meso-bromination strategy, followed by similar coupling sequences [135]. Due to the versatility of the 3,13-dibromobacteriochlorin building block 19, various solubilization motifs could be introduced to this scaffold. Thus, ammonium (compounds 22 and 23, Figure 11), carboxylate (compound 92, Figure 11), phosphonate (compound 132, Figure 11) and PEG (compound 176, Figure 11) solubilizing motifs were introduced by coupling with suitable arylboronic esters as shown in Scheme 54. The products were compared by Lindsey and co-workers according to several notable parameters [65] (Table 2). The method of purification of the water-soluble adducts, the solubility of the compounds (as measured by the change in UV-vis absorption spectra over a 1000-fold concentration range), the full width at half-maximum (FWHM) of the longest wavelength of absorption and emission, and the stability of the chromophores in the light and dark.Overall, it was found that either the cationic ammonium or neutral-PEGylated species were the most promising derivatives because of their facile purification (precipitation), their amenability to further bioconjugation reactions, and good dark and light stabilities. The PEGylated derivatives were also shown to display very little aggregation, as demonstrated by the sharp absorbance and emission peaks in their optical spectra over a 1000-fold concentration range.

Molecules 2017, 22, 980 35 of 46

OR OH H3C H3C O O CH3 CH3 F C O CF 1. 3 3 H3C 172a: R = OH H3C O CH N N CH3 N N 3 2. HO-R H H H 172b: R = O H O OH N N N N H3C OH H3C 172c: R = OH

O N O O N O 172d: R = CO2H OCH3 CO2H OCH3 OCH3 171 172 Scheme 52. Hydrophilic bacteriochlorin cycloimides, as described by the group of Feofanov [163].

Molecules 2017, 22, 980 35 of 47 The meso-Suzuki coupling method developed by Lindsey and co-workers and utilized for the introduction of a variety of solubilization groups to hydroporphyrins (cf. Schemes 5, 12 and 26) was Bacterio-chlorinalso utilized173 for wasthe introduction prepared by of Suzuki PEG groups coupling to bacteriochlorin of the corresponding 173 (Schememeso -bromobacteriochlorin53) [164]. Bacterio- Moleculeschlorin 2017173 , was22, 980 prepared by Suzuki coupling of the corresponding meso-bromobacteriochlorin36 with of 46 with an aryl-boronic ester bearing two unprotected aldehyde functional groups. The aldehyde an aryl-boronic ester bearing two unprotected aldehyde functional groups. The aldehyde functionalitiesfunctionalities were were PEGylated PEGylated by by reductivereductive aminat aminationion with with an amine-terminated an amine-terminated PEG to PEG afford to the afford the water-solublewater-soluble PEGylatedPEGylated bacteriochlorin bacteriochlorin 174174. .

Scheme 53. PEGylated bacteriochlorins formed by reductive amination, as described by the group of Scheme 53. PEGylated bacteriochlorins formed by reductive amination, as described by the group of Lindsey [164]. Lindsey [164]. Another representative example for the introduction of PEG groups via Suzuki coupling of Anotherdibromobacteriochlorin representative 19 with example a Boc-protected for the introduction amine-derivatized of PEG boronic groups ester,via followed Suzuki by couplingBoc- of dibromobacteriochlorindeprotection under standard19 with conditio a Boc-protectedns, afforded diaryl amine-derivatized bacteriochlorin 175 boronic carrying ester, two followed amine by Boc-deprotectiongroups. The amines under were standard PEGylated conditions, by amide formation afforded with diaryl a PEG-NHS bacteriochlorin ester to afford 175bacteriochlorincarrying two amine176 groups. (Scheme The 54) [135]. amines Derivatives were PEGylated bearing bioconjugatable by amide formation tethers (177 with) and a (178 PEG-NHS) were also ester prepared to afford using a regioselective meso-bromination strategy, followed by similar coupling sequences [135]. bacteriochlorin 176 (Scheme 54)[135]. Derivatives bearing bioconjugatable tethers (177) and (178) Due to the versatility of the 3,13-dibromobacteriochlorin building block 19, various solubilization were also prepared using a regioselective meso-bromination strategy, followed by similar coupling motifsFigure could 11. be Molecular introduced structures to this of ascaffold. variety of Thus, examples ammonium of water-soluble (compounds bacteriochlorins 22 and derived23, Figure by 11), sequences [135]. carboxylateSuzuki coupling(compound (Scheme 92, Figure 54). 11), phosphonate (compound 132, Figure 11) and PEG (compound 176, Figure 11) solubilizing motifs were introduced by coupling with suitable arylboronic esters as shown in Scheme 54. H3C(OH2CH2C)4 O CH3(OCH2CH2)4 H NHBoc H2N H N The productsH3 C were comparedH N by Lindsey and co-workers according to several notable O 2 N H3C O B parameters [65] (TableH C 2). The method of purification of the water-soluble adducts, the solubility of 3 O O O Br OCH OCH3 OCH3 3 H3C NHBoc H3C(OH2CH2C)4 the compoundsCH (as measured by the change CHin3 UV-vis absorption spectra overCH3 a 1000-fold 3 1. Pd(PPh ) , Cs CO , O N 3 4 2 3 CH CH3 PhCH /DMF (2:1), 90 °C CH3 3 concentrationN N range), the3 full width at Nhalf-maximumN (FWHM) of the NlongestN wavelength of H 2. TFA/CH2Cl2 (2:3) H DMF O H absorptionH and emission, and the stability ofH the chromophores in the light andH dark.Overall, it was N N N N N N H C H C foundH3C that either the cationic ammonium3 or neutral-PEGylated species3 were the most promising H C H3C 19 H3C 175 3 176 derivatives Brbecause of their facile purification (precipitation), their amenability to further

bioconjugation reactions, and good dark and light stabilities. The PEGylated derivatives Owere also H C(OH CH C) N 3 2 2 4 NH2 NH H O 2 N H shown to displayCH3(OCH very2CH2 )little4 aggregation,H as demonstrated by the sharp absorbanceO and emission(CH CH O)peaksCH H N 2 2 4 3 in their optical spectra overN a 1000-fold concentration range.O (CH2CH2O)4CH3 O H3C(OH2CH2C)8 N OCH3 H MeO2C OCH3 CH3 CH3

CH3 H CH N N N 3 N O H N H CH (OCH CH ) H 3 2 2 8 H (CH2CH2O)8CH3 N N O N N N H3C H3C H H3C H3C H O N O N 177 178 O (CH CH O) CH N O 2 2 8 3 HO2C N H O H CO2H (CH2CH2O)4CH3 (CH2CH2O)4CH3 Scheme 54. β-Substituted PEGylated synthetic bacteriochlorins via Suzuki coupling, as described by Scheme 54. β-Substituted PEGylated synthetic bacteriochlorins via Suzuki coupling, as described by the group of Lindsey [135]. the group of Lindsey [135].

Due to the versatility of the 3,13-dibromobacteriochlorin building block 19, various solubilization motifs could be introduced to this scaffold. Thus, ammonium (compounds 22 and 23, Figure 11), carboxylate (compound 92, Figure 11), phosphonate (compound 132, Figure 11) and PEG (compound

Molecules 2017, 22, 980 36 of 47

176, Figure 11) solubilizing motifs were introduced by coupling with suitable arylboronic esters as shownMolecules in Scheme 2017, 22 , 54980. 36 of 46

Figure 11. Molecular structures of a variety of examples of water-soluble bacteriochlorins derived by Figure 11. Molecular structures of a variety of examples of water-soluble bacteriochlorins derived by Suzuki coupling (Scheme 54). Suzuki coupling (Scheme 54).

H3C(OH2CH2C)4 CH (OCH CH ) O H N 3 2 2 4 H N H C NHBoc 2 H The products were3 comparedH2N by Lindsey and co-workers according to several notable O N H3C O B H C parameters [65] (Table3 2).O The method of puriﬁcation of the water-solubleO O adducts, the solubility of the Br OCH OCH3 OCH3 3 H3C NHBoc H3C(OH2CH2C)4 CH CH3 CH3 compounds (as measured3 1. Pd(PPh by) the, Cs CO change, in UV-vis absorption spectraO N over a 1000-fold concentration 3 4 2 3 CH CH3 PhCH /DMF (2:1), 90 °C CH3 3 N N 3 N N N N range), the fullH width at2. half-maximum TFA/CH2Cl2 (2:3) (FWHM)H of the longestDMF wavelengthO ofH absorption and emission, H H H and the stabilityN N of the chromophores in theN lightN and dark.Overall, it was foundN N that either the cationic H C H3C H3C 3 19 H C 175 H C 176 ammoniumH3C or neutral-PEGylated species3 were the most promising derivatives3 because of their facile Br puriﬁcation (precipitation), their amenability to further bioconjugation reactions, and good dark and O H C(OH CH C) N 3 2 2 4 NH2 NH H light stabilities. The PEGylated derivativesO were2 also shown to display veryN H little aggregation, as CH3(OCH2CH2)4 H O (CH CH O) CH H N 2 2 4 3 demonstrated by the sharpN absorbance and emission peaksO in their optical spectra(CH2CH2O)4CH over3 a 1000-fold O H3C(OH2CH2C)8 concentration range. N OCH3 H MeO2C OCH3 With the PEGylated derivativesCH appearing3 to be among the mostCH3 promising motifs for CH3 H CH N N N 3 N O H N H solubilization, Lindsey and co-workers setCH out(OCH CH to) prepare a series of PEGylated chlorins and H 3 2 2 8 H (CH2CH2O)8CH3 N N O N N N bacteriochlorins (with optionsH3C for bioconjugation) using a rangeH3C of synthetic methodologiesH [135,136]. H3C H3C One such example for the direct, late-stage PEGylation of chlorin derivativesH was the azide-alkyne O N O N 177 178 Huisgen-cycloaddition (click) reaction betweenO an alkyne-substituted porphyrin(CH CH O) orCH chlorin and N O 2 2 8 3 HO2C N H an azide-terminated PEG. O H CO2H (CH2CH2O)4CH3 This strategy was employed to(CH perform2CH2O)4CH3 a direct PEGylation of trans-AB porphyrin 179 (Scheme 55) to affordScheme the PEGylated 54. β-Substituted porphyrin PEGylated180 synthetic[165]. bacteriochlorins Along analogous via Suzuki routes, coupling, synthetic as described chlorins by 181 and 182 werethe group prepared of Lindsey from [135]. alkyne-substituted meso-aryl groups and subsequent reactions with PEG-azides [136]. In addition, an aldol condensation method was developed to directly introduce an aryl group bearing three PEG chains to the β-positions of a β-diacetyl-substituted chlorin 183. Reaction of 183 with a PEG-substituted aryl aldehyde formed the porphyrin-chalcone 184 (Scheme 56)[136]. The absorption spectrum of the PEGylated chlorin-chalcone 184 was broadened in pure water, indicating its aggregation. Molecules 2017, 22, 980 37 of 46

Table 2. Comparison of relevant properties concerning hydrophilicity of a series of structurally similar synthetic bacteriochlorins, as described by the group of Lindsey [65].

FWHM (abs, Stability in Stability in Compounds Purification Method a Water-Solubility b fl) (nm) c Light (%) d Dark (%) e 132 reverse phase chromatography 0.46 μM–460 μM 26, 30 85 >95 ppt, washing with 92 0.32 μM–320 μM 26, 26 96 >95 hexanes/MeOH (49:1) 22 ppt, washing with Et2O/THF (1:1) 0.24 μM–240 μM 26, 26 82 >95 23 ppt.,washing with Et2O/THF (1:1) 0.18 μM–180 μM 40, 26 96 >95 ppt, washing with 176 0.43 μM–430 μM 22, 23 95 >95 hexanes/CH2Cl2 (19:1) a For the final step of the synthesis; b measured in aqueous media (PBs except 176, water) by the Molecules 2017absorption, 22, 980 upon reciprocal change in concentration and path length; c 1 μM in PBS. FWHM = full 37 of 47 width at half maximum of the longest wavelength band of absorption or emission, an indicator of aggregation; d The % remaining of a 1 μM solution in PBS after several hours of absorption and Tablefluorescence 2. Comparison studies. of e relevant The % remaining properties of a, concerning 1 μM solution hydrophilicity in PBS allowed of ato series stand ofin the structurally dark at 4 °C similar

syntheticfor 48 bacteriochlorins, h (as determined by as absorption described intensity by the group of Qy band. of Lindsey [65].

With the PEGylated derivatives appearinga to be among the mostb FWHM promising (abs, motifsStability for solubilization, in Stability in Compounds Purification Method Water-Solubility c d e Lindsey and co-workers set out to prepare a series of PEGylated chlorinsfl) (nm) and bacteriochlorinsLight (%) Dark (with (%) options132 for bioconjugation) reverse phase chromatographyusing a range of synthetic 0.46 µmethM–460odologiesµM [135,136]. 26, 30 One such 85 example for >95the ppt, washing with direct,92 late-stage PEGylation of chlorin derivative0.32s wasµM–320 the azide-alkyneµM 26, 26Huisgen-cycloaddition 96 (click) >95 hexanes/MeOH (49:1) reaction22 between ppt, washing an alkyne-substituted with Et2O/THF (1:1) porphyri 0.24n orµM–240 chlorinµM and an 26,azide-terminated 26 82 PEG. >95 23This strategy ppt.,washing was employed with Et2O/THF to perform (1:1) a direct 0.18 PEGylationµM–180 µM of trans 40,-AB 26 porphyrin 96 179 (Scheme>95 55) ppt, washing with to176 afford the PEGylated porphyrin 180 [165]. Along0.43 µ analogousM–430 µM routes, 22, synthetic 23 chlorins 95 181 and >95182 hexanes/CH2Cl2 (19:1) were prepared from alkyne-substituted meso-aryl groups and subsequent reactions with PEG-azides a For the final step of the synthesis; b measured in aqueous media (PBs except 176, water) by the absorption upon reciprocal[136]. In addition, change in an concentration aldol condensation and path length; methodc 1 wasµM indeveloped PBS. FWHM to =directly full width introduce at half maximum an aryl group of the longestbearing wavelength three PEG band chains of absorptionto the β-positions or emission, of a an β indicator-diacetyl-substituted of aggregation; chlorind The %183 remaining. Reaction of aof 1 183µM solutionwith a inPEG-substituted PBS after several aryl hours aldehyde of absorption formed and fluorescence the porphyrin-chalcone studies. e The % remaining184 (Scheme of a, 156)µM [136]. solution The in ◦ PBSabsorption allowed spectrum to stand in of the the dark PEGylated at 4 C for chlorin-chalcone 48 h (as determined 184 by absorptionwas broadened intensity in ofpure Qy band.water, indicating its aggregation.

SchemeScheme 55. PEGylated 55. PEGylated porphyrins porphyrins and and chlorins chlorins prepared prepared through through clickclick chemistry, as as described described by by the the group of Lindsey [136]. group of Lindsey [136]. Molecules 2017, 22, 980 38 of 46

O(CH2CH2O)4CH3 O(CH CH O) CH 2 2 4 3 CH3(OCH2CH2O)4O

O O H3C CH3(OCH2CH2O)4O H3C(OH2CH2C)4O O(CH2CH2O)4CH3 CHO NaOH, MW, N N N N EtOH, 80 °C H H CO Me CO H H 2 H 2 N N N N H3C H3C

H3C H3C O(CH CH O) CH CH 2 2 4 3 183 O 3 184 O

O(CH2CH2O)4CH3 H3C(OH2CH2C)4O Scheme 56. PEGylated chlorins prepared by Aldol-condensation of β-diacetyl chlorin, as described Scheme 56. PEGylated chlorins prepared by Aldol-condensation of β-diacetyl chlorin, as described by by the group of Lindsey [136]. the group of Lindsey [136]. Lindsey and co-workers also used an amide coupling of an alkyl-amine substituted bacteriochlorin Lindseywith a PEG-NHS and co-workersester to produce also PEGylated used bacteriochlorin an amide coupling 186 (Scheme of 57) an [135]. alkyl-amine The β-functionalized substituted bacteriochlorinbacteriochlorin with 185 a was PEG-NHS prepared esterby Sonogashira to produce coupling PEGylated and subsequent bacteriochlorin reduction186 of the(Scheme alkynes. 57Boc-)[135]. The βdeprotection-functionalized was followed bacteriochlorin by saponificiation185 was to preparedfurnish the by amine Sonogashira and acid-derivatized coupling intermediate, and subsequent which was reacted with a PEG-NHS ester to provide the PEGylated bacteriochlorin 186. The carboxylic reduction of the alkynes. Boc-deprotection was followed by saponiﬁciation to furnish the amine acid functionality on this chromophore is available for bioconjugation. and acid-derivatized intermediate, which was reacted with a PEG-NHS ester to provide the H PEGylated bacteriochlorin 186. The carboxylic1. Pd/C, H2, EtOAc, acid EtOH, functionality r.t. H on this chromophore is available (CH CH O) CH BocN 2. TFA/CH2Cl2 (1:5) N 2 2 8 3 for bioconjugation. 3. aq NaOH/THF/MeOH (1:2:1) 4. Cs2CO3, DMF, O O O OCH3 OCH3 H3C(OH2CH2C)8 CH3 O N CH3 CH N N 3 N N CH3 H O H H H N N N N H C H3C 3 H3C H3C

185 186

CO2H CO2CH3 Scheme 57. PEGylated bacteriochlorins bearing a bioconjugatable tether prepared by amide coupling, as described by the group of Lindsey [135].

5. Summary and Outlook In summary, significant progress has been made in the past decades toward the preparation of water-soluble porphyrins and hydroporphyrins. A wide range of options are available for their solubilization in aqueous media. Cationic, anionic or neutral groups may be introduced in regio- and chemoselective fashion. Their number and positioning has major influences on the solubility of the derivatized porphyrin, whereby swallowtail approaches stand out as seemingly particularly effective in mediating water-solubility with a moderate concomitant increase in molecular weight. All solubilizing functionalities can be introduced at early stages of the synthesis of the target compound—generally in protected form—or at late stages. The late-state introduction of the solubilizing motif(s) reduces the number of difficult chromatographic steps needed in the synthetic sequence; and these polar moieties and/or their water-solubility generally complicate their isolation and purification. Irrespective of the timing of the introduction of the solubilizing groups, multiple linking strategies are available. As far as flexibility and ease of implementation, PEGylation strategies stand out because they generate neutral chromophores of good solubility, the PEG chains are chemically stable, the versatility of the linking moieties that can be used to link PEG chains to the chromophore, and the facility of the work-up conditions once the PEG chains are established. A combined approach using both ionic and PEG groups may also have its merits in cases where the introduction of short PEGs was not enough to solubilize the macrocycle.

Molecules 2017, 22, 980 38 of 46

O(CH2CH2O)4CH3 O(CH CH O) CH 2 2 4 3 CH3(OCH2CH2O)4O

O O H3C CH3(OCH2CH2O)4O H3C(OH2CH2C)4O O(CH2CH2O)4CH3 CHO NaOH, MW, N N N N EtOH, 80 °C H H CO Me CO H H 2 H 2 N N N N H3C H3C

H3C H3C O(CH CH O) CH CH 2 2 4 3 183 O 3 184 O

O(CH2CH2O)4CH3 H3C(OH2CH2C)4O Scheme 56. PEGylated chlorins prepared by Aldol-condensation of β-diacetyl chlorin, as described by the group of Lindsey [136].

Lindsey and co-workers also used an amide coupling of an alkyl-amine substituted bacteriochlorin with a PEG-NHS ester to produce PEGylated bacteriochlorin 186 (Scheme 57) [135]. The β-functionalized bacteriochlorin 185 was prepared by Sonogashira coupling and subsequent reduction of the alkynes. Boc- deprotection was followed by saponificiation to furnish the amine and acid-derivatized intermediate, Moleculeswhich2017 was, 22, 980reacted with a PEG-NHS ester to provide the PEGylated bacteriochlorin 186. The carboxylic38 of 47 acid functionality on this chromophore is available for bioconjugation.

H 1. Pd/C, H2, EtOAc, EtOH, r.t. H (CH CH O) CH BocN 2. TFA/CH2Cl2 (1:5) N 2 2 8 3 3. aq NaOH/THF/MeOH (1:2:1) 4. Cs2CO3, DMF, O O O OCH3 OCH3 H3C(OH2CH2C)8 CH3 O N CH3 CH N N 3 N N CH3 H O H H H N N N N H C H3C 3 H3C H3C

185 186

CO2H CO2CH3

SchemeScheme 57. PEGylated 57. PEGylated bacteriochlorins bacteriochlorins bearing bearing a bioconju bioconjugatablegatable tether tether prepared prepared by amide by amide coupling, coupling, as described by the group of Lindsey [135]. as described by the group of Lindsey [135]. 5. Summary and Outlook 5. Summary and Outlook In summary, significant progress has been made in the past decades toward the preparation of Inwater-soluble summary, porphyrins significant and progress hydroporphyrins. has been made A wide in therange past of options decades are toward available the for preparation their of water-solublesolubilizationporphyrins in aqueous media. and hydroporphyrins. Cationic, anionic or neutral A wide groups range may of options be introduced are available in regio- and for their solubilizationchemoselective in aqueous fashion. media. Their number Cationic, and anionic positionin or neutralg has major groups influences may be on introduced the solubility in of regio- the and chemoselectivederivatized porphyrin, fashion. Their whereby number swallowtail and positioning approaches stand has major out as influencesseemingly particularly on the solubility effective of the in mediating water-solubility with a moderate concomitant increase in molecular weight. All solubilizing derivatized porphyrin, whereby swallowtail approaches stand out as seemingly particularly effective in functionalities can be introduced at early stages of the synthesis of the target compound—generally mediating water-solubility with a moderate concomitant increase in molecular weight. All solubilizing in protected form—or at late stages. The late-state introduction of the solubilizing motif(s) reduces functionalitiesthe number can of bedifficult introduced chromatographic at early stages steps of ne theeded synthesis in the synthetic of the target sequence; compound—generally and these polar in protectedmoieties form—or and/or attheir late stages.water-solubility The late-state generally introduction complicate of thetheir solubilizing isolation and motif(s) purification. reduces the numberIrrespective of difficult of the chromatographic timing of the introduction steps needed of the in solubilizing the synthetic groups, sequence; multiple and linking these polarstrategies moieties and/orare theiravailable. water-solubility As far as flexibility generally and complicate ease of implementation, their isolation andPEGylation purification. strategies Irrespective stand out of the timingbecause of the they introduction generate neutral of the solubilizingchromophores groups, of good multiple solubility, linking the PEG strategies chains are are chemically available. stable, As far as flexibilitythe versatility and ease of of the implementation, linking moieties PEGylationthat can be used strategies to link standPEG chains out because to the chromophore, they generate and neutral chromophoresthe facility ofof goodthe work-up solubility, conditions the PEG once chains the PEG are chains chemically are established. stable, the A versatility combined ofapproach the linking using both ionic and PEG groups may also have its merits in cases where the introduction of short moieties that can be used to link PEG chains to the chromophore, and the facility of the work-up PEGs was not enough to solubilize the macrocycle. conditions once the PEG chains are established. A combined approach using both ionic and PEG groups may also have its merits in cases where the introduction of short PEGs was not enough to solubilize the macrocycle. Even though the toolbox for the synthetic chemist to affect water-solubility is already extensive, the continued development of solubilizing strategies that are mild, selective, and introduce chemically robust solubilization motifs to porphyrins is vital to the field for these versatile chromophores to realize their full potential in the many technical and biomedical applications that take place in aqueous media.

Acknowledgments: This work was supported by the US National Science Foundation through grant CHE-1465133 and the University of Connecticut. Author Contributions: M.L. and C.B. wrote the paper to equal parts. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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