Progress in the Chemistry of Macrocyclic Meroterpenoids

Review Progress in the Chemistry of Macrocyclic Meroterpenoids

Dmitriy N. Shurpik 1 , Alan A. Akhmedov 1 , Peter J. Cragg 2 , Vitaliy V. Plemenkov 1 and Ivan I. Stoikov 1,* 1 A.M. Butlerov Chemical Institute, Kazan Federal University, 18 Kremlevskaya Street, Kazan 420008, Russia; [email protected] (D.N.S.); [email protected] (A.A.A.); [email protected] (V.V.P.) 2 School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Moulsecoomb Brighton, East Sussex BN2 4GJ, UK; [email protected] * Correspondence: [email protected]; Tel.: +7-8432-337463

Received: 17 October 2020; Accepted: 12 November 2020; Published: 15 November 2020

Abstract: In the last decade, the chemistry of meroterpenoids—conjugated molecules formed from isoprenyl fragments through biosynthetic pathways—has developed rapidly. The class includes some natural metabolites and fully synthetic fragments formed through nonbiological synthesis. In the field of synthetic receptors, a range of structures can be achieved by combining fragments of different classes of organic compounds into one hybrid macrocyclic platform which retains the properties of these fragments. This review discusses the successes in the synthesis and practical application of both natural and synthetic macrocycles. Among the natural macrocyclic meroterpenoids, special attention is paid to isoprenylated flavonoids and phenols, isoprenoid lipids, prenylated amino acids and alkaloids, and isoprenylpolyketides. Among the synthetic macrocyclic meroterpenoids obtained by combining the “classical” macrocyclic platforms, those based on cyclodextrins, together with meta- and paracyclophanes incorporating terpenoid fragments, and meroterpenoids obtained by macrocyclization of several terpene derivatives are considered. In addition, issues related to biomedical activity, processes of self-association and aggregation, and the formation of host–guest complexes of various classes of macrocyclic merotenoids are discussed in detail.

Keywords: terpenoids; macrocyclic systems; associations; host–guest systems

1. Introduction In recent years, various classes of natural compounds have found application in clinical medicine as an alternative to classical synthetic drugs [1]. This is primarily due to the availability and variety of natural organic compounds exhibiting a wide range of biological activity and having a significantly smaller number of side effects [1,2]. A special place among this variety of natural compounds is occupied by several separate classes of natural compounds of mixed biogenetic nature–conjugated molecules formed from isoprenyl fragments through biosynthetic pathways together with other natural metabolites (flavonoids, alkaloids, etc.), synthesized by nonisoprenoid pathways [3,4]. These compounds, in which the isoprenyl, or more often a hemi-, mono-, di- or triterpene, fragment is included in their composition as a functional group, are designated by the prefix mero-, and thus termed the meroterpenoids [2,4]. In the past decade, there has been intensive development of the chemistry of meroterpenoids [5,6]. This is primarily due to the unique properties of these compounds. It is worth noting that the role of plant-derived raw materials as a source of natural meroterpenoids is gradually giving way to synthetic methods of production [7] due to the demand for large quantities of drugs for practical use. It is safe to say that about 40% of all-natural compounds used in medicine are obtained biosynthetically or using

Plants 2020, 9, 1582; doi:10.3390/plants9111582 www.mdpi.com/journal/plants Plants 2020, 9, 1582 2 of 26 enzymatic catalysis [8]. For example, nonribosomal peptide synthetases, terpene synthases, ribosomally synthesized and post-translational genes are used in the biotechnological process of biosynthesis of macrocyclic meroterpenoid depsipeptides [9]. Mono-, di-, triterpene secondary metabolites are isolated (<90%) from natural raw materials; however, they are practically not used individually. They are further modified using fully synthetic methods [10]. In this regard, the strategy of synthesis and functionalization of various compounds with terpenoid fragment pharmacophores, which increase their biological activity and reduce toxicity, has become relevant [11]. In the field of macrocyclic compounds, the combination of different structures can be achieved by combining fragments of several classes of organic compounds into one hybrid macrocyclic platform. Such macrocyclic meroterpenoids can retain and combine the properties of these fragments. Terpenoid residues are attractive pharmacophore fragments, the introduction of which into the structure of the macrocyclic platform can contribute to a decrease in toxicity, an increase in the affinity for the cell membrane, as well as the processes of self-association and aggregation. Macrocyclic meroterpenoids can be divided into two main classes. The first is natural macrocycles obtained by conjugated biosynthesis and isolated from natural raw materials. In this case, macrocyclization is carried out by enzyme-mediated cascade reactions [12]. The second class of macrocyclic meroterpenoids comprises synthetic macrocycles obtained by assembling macrocyclic scaffolds by cyclization of individual terpene fragments, or by introducing terpene fragments through various synthetic methods into the macrocyclic platform [4,7].

2. Natural Macrocyclic Meroterpenoids Among natural macrocyclic meroterpenoids, isoprenylated flavonoids and phenols [6,13], isoprenoid lipids [14], prenylated amino acids [15], and isoprenylpolyketide alkaloids [5] have been most extensively studied. All of these macrocyclic meroterpenoids are derived directly from natural raw materials. Today, there are a number of methods that allow the isolation and characterization of natural meroterpenoids, among them: chromatographic technique, solvent extraction, membrane separation, distillation techniques, supercritical fluid fractionation, and others. All of these methods have both advantages and disadvantages. Thus, chromatographic techniques can provide high purity of key substances; at the same time, this is a laborious method that requires sophisticated equipment and entails low yields of target products. Extraction techniques are the easiest to implement but are associated with environmental pollution with organic solvents and also involve expensive recovery operations. Membrane separation is a highly selective method for meroterpenoids disengagement and is less labor-intensive consuming than others. However, the liquid–liquid interface is unstable, which causes a short membrane life. Distillation techniques are suitable for preparation of high purification and enriched fractions; however, these methods involve risk of implosion. The supercritical fluid fractionation is green chemistry, highly selective, and provides a high yield of target products. However, this is the most expensive method, requiring special operating system security, a large number of configurable factors, and the addition of organic modifiers [16]. The formation of macrocyclic secondary metabolites during biosynthesis is a thermodynamically beneficial process since a whole series of final biochemical metabolic products can be obtained from one macrocyclic metabolite by transannular cyclization of the macrocyclic structure [17]. Thus, Zhang et al. [18] showed that alcohol dehydrogenase (IkaC) catalyzes an unusual reaction (Figure1) of reductive cyclization of compound 1 to ikarugamycin (2) with the formation of an inner five-membered ring [18]. Ikarugamycin (2) is isolated from strains of Streptomyes bacteria. In addition to strong antiprotozoal, antiulcer, antibacterial, antiviral, cytotoxic and apoptosis-inducing activities, it has also been reported that 2 inhibits the penetration of oxidized low-density lipoproteins into macrophage cells, thereby preventing the formation of atherosclerotic plaques, and clathrin-dependent endocytocytosis, which opens up the possibility of using 2 as a therapeutic agent [18]. Plants 2020, 9, 1582 3 of 26 Plants 2020,, 9,, xx FORFOR PEERPEER REVIEWREVIEW 3 of 27

Figure 1. Formation of ikarugamycin (2).

The study of thethe formationformation of secondarysecondary metabolites in fungi of thethe genusgenus StachybotryStachybotry, namelynamely mycelial cultureculture DSMDSM 12880 12880 (chemotype (chemotype S), S), led led to to the the discovery discover ofy threeof three new new meroterpenoids meroterpenoids3-5 [ 133-5], which[13], which contain contain a fragment a fragment of the chromene of the chromene ring with ring side with isoprenoid side isop fragments.renoid fragments. Taking into Taking account into the biosyntheticaccount the biosynthetic pathway, it can pathway, be assumed it can that be stachibotrichromenassumed that stachibotrichromen C (5) (Figure2) isC the(5) (Figure ﬁnal product 2) is the of thefinal process product and of is the formed process through and is the formed intermediate through stachibotrichromen the intermediate stachibotrichromen A (3) and stachibotrichromen A (3) and B(stachibotrichromen4) (Figure2). From B the (4) point(Figure of 2). view From of cytotoxicity, the point of substancesview of cytotoxicity,3 and 4 exhibit substances a moderate 3 and cytotoxic4 exhibit eaﬀ moderateect on HepG2 cytotoxiccells after effect 24 on h ofHepG2 exposure, cells after while 245 hdid of notexposure, exhibit while cytotoxicity 5 did not over exhibit the concentration cytotoxicity rangeover the studied concentration (0.1–100 µrangeM) [13 studied]. (0.1–100 μM) [13].

FigureFigure 2.2. Structure ofof stachybotrichromensstachybotrichromens 33-5–5.

Li’s group [19] discovered two new macrocyclic meraterpenoids derived from isoindolone from Li’s group [19] discovered two new macrocyclic meraterpenoids derived from isoindolone from the culture of the endophytic fungus Emericella nidulans HDN12-249. Emericellolides A-C (6–8) the culture of the endophytic fungus Emericella nidulans HDN12-249. Emericellolides A-C (6-8) (Figure3) possess an unprecedented macrolide skeleton. The resulting compounds have potential (Figure 3) possess an unprecedented macrolide skeleton. The resulting compounds have potential antitumor activity. antitumor activity.

Figure 3. Structures of emercellolides 6–8. Figure 3. Structures of emercellolides 6-8.

The Diels–Alder reaction is one of the most demanded synthetic transformations for the creation of complex natural compounds [20]. However, only a few examples of its use in enzyme-mediated

Plants 2020, 9, x FOR PEER REVIEW 4 of 27 Plants 2020, 9, 1582 4 of 26 cascade reactions of macrocyclic meroterpenoids have been described [21,22]. Thus, in 2019, Houk et al. [23]The reported Diels–Alder on the reaction intermolecular is one of thehetero-Diels most demanded–Alder syntheticreaction in transformations the biosynthesis for of the macrocyclic creation of Plants 2020, 9, x FOR PEER REVIEW 4 of 27 sesquiterpenes.complex natural It compounds is noteworthy [20]. that However, neosetofomon only a few B examples (12), isolated of its as use an in optically enzyme-mediated pure compound cascade from various mushrooms, can be obtained via one or two tandem hetero-Diels–Alder reactions. reactionscascade reactions of macrocyclic of macrocyclic meroterpenoids meroterpenoids have been have described been described [21,22]. [21,22]. Thus, in Thus, 2019, in Houk 2019, etHouk al. [ 23et ] Neosetofomon B (12) has a unique central 11-membered macrocycle consisting of a dihydropyran reportedal. [23] reported on the on intermolecular the intermolecular hetero-Diels–Alder hetero-Diels–Alder reaction reaction in in the the biosynthesis biosynthesis of macrocyclic macrocyclic ring linked to tropolone 10 and has very strong antitumor activity at the nanomolar level. It has been sesquiterpenes.sesquiterpenes. ItIt isis noteworthynoteworthy that neosetofomon B B ( (1212),), isolated isolated as as an an optically optically pure pure compound compound shown (Figure 4) that the enzyme EupfF catalyzes the dehydration of hydroxymethyl-containing fromfrom variousvarious mushrooms,mushrooms, cancan bebe obtainedobtained via on onee or two tandem tandem hetero-Diels–Alder hetero-Diels–Alder reactions. reactions. tropolone 9 to form the reactive o-quinone tropolone 10. The EupfF enzyme is also able to NeosetofomonNeosetofomon B B ( 12(12) has) has a uniquea unique central central 11-membered 11-membered macrocycle macrocycle consisting consisting of aof dihydropyran a dihydropyran ring stereoselectively control the subsequent intermolecular hetero-Diels–Alder reaction with (1E, 4E, 8Z)- linkedring linked to tropolone to tropolone10 and 10 has and very has strong very strong antitumor antitumor activity activity at the nanomolarat the nanomolar level. Itlevel. has beenIt has shown been humulenol (11), obtained from farnesyl pyrophosphate (FPP) by the action of the terpene cyclase (Figureshown4 )(Figure that the 4) enzyme that theEupfF enzymecatalyzes EupfF catalyzes the dehydration the dehydration of hydroxymethyl-containing of hydroxymethyl-containing tropolone enzyme. The result is an enantiomerically pure neosetofomon B (12) (Figure 4), to which the addition 9tropoloneto form the 9 reactiveto form o-quinonethe reactive tropolone o-quinone10 .tropolone The EupfF 10enzyme. The EupfF is also enzyme able to stereoselectivelyis also able to of an excess of 10 leads to upenifeldine (13), a neosetofomon containing two dihydropyran fragments. controlstereoselectively the subsequent control intermolecular the subsequent hetero-Diels–Alder intermolecular hetero-Diels–A reaction withlder (1E, reaction 4E, 8Z)-humulenol with (1E, 4E, 8Z)- (11), obtainedhumulenol from (11 farnesyl), obtained pyrophosphate from farnesyl (FPP pyrophosphate) by the action ( ofFPP the) byterpene the action cyclase ofenzyme. the terpene The resultcyclase is anenzyme. enantiomerically The result pureis an neosetofomonenantiomerically B ( 12pure) (Figure neosetofomon4), to which B (12 the) (Figure addition 4), of to an which excess the of addition10 leads toof upenifeldine an excess of 10 (13 leads), a neosetofomon to upenifeldine containing (13), a neosetofomon two dihydropyran containing fragments. two dihydropyran fragments.

Figure 4. Biosynthetic way for the production of neosetofomon B (12) and upenifeldin (13).

A series of new isoprenylated phenols was isolated by Liu, An et al. [24] from Psidium guajava. The spatial structuresFigureFigure 4.4. of BiosyntheticBiosynthetic the meroterpenoids wayway forfor the productionpsiguajavadial of neosetofomon A (14) and B BB ( (12 12(15)) and and) (Figure upenifeldin upenifeldin 5) have ( (1313). ).been fully established using extensive spectroscopic methods and theoretical calculations. Flow cytometric analysis showedAA series thatseries the ofof novel newnew isoprenylated meroterpenoids phenols phenols 14 and was 15 was can isolated isolated induce by apoptosis byLiu, Liu, An Anet in al. HCT116 et [24] al. [from24 cells.] from Psidium ThesePsidium guajavadata guajavasuggest. The . thatThespatial meroterpenoids spatial structures structures of from the of meroterpenoidsguava the meroterpenoids fruits can psiguajavadialbe us psiguajavadialed for the Adevelopment (14) A and (14 )B and of(15 anticancer) B(Figure (15) (Figure 5)agents. have5) havebeen beenfully fullyestablishedA established unique using macrocyclic using extensive extensive spectroscopic isoprenylate spectroscopic methodsd phenol, methods and theoreticalnapyradiomycin and theoretical calculations. calculations.D1 Fl(16ow), cytometriccontaining Flow cytometric analysis a 14- memberedanalysisshowed that showed cyclic the novel ether that meroterpenoids the ring, novel was meroterpenoidsisolated 14 and from 15 can Streptomyces induce14 and apoptosis15 cansp. strain induce in HCT116 CA-271078 apoptosis cells. These [25]. in HCT116 dataThe suggestauthorscells. reportThesethat meroterpenoids datathat meroterpenoid suggest from that meroterpenoidsguava 16 (Figure fruits can5) exhibited be from used guavafor significant the fruitsdevelopment inhibitory can be of used anticancer activity for the against agents. development methicillin- of resistantanticancerA uniqueStaphylococcus agents. macrocyclic aureus , isoprenylateMycobacteriumd phenol,tuberculosis napyradiomycin and HepG2. D1 (16), containing a 14- membered cyclic ether ring, was isolated from Streptomyces sp. strain CA-271078 [25]. The authors report that meroterpenoid 16 (Figure 5) exhibited significant inhibitory activity against methicillin- resistant Staphylococcus aureus, Mycobacterium tuberculosis and HepG2.

Figure 5. StructuresStructures of of psiguajavadials psiguajavadials A ( 14),), B ( 15) and napyradiomycin D1 ( 16).

A unique macrocyclic isoprenylated phenol, napyradiomycin D1 (16), containing a 14-membered Another unique natural source of macrocyclic meroterpenoids is archaeal lipids consisting of cyclic ether ring, was isolated from Streptomyces sp. strain CA-271078 [25]. The authors report methylated isoprenoidFigure 5. Structures chains, whic of psiguajavadialsh are ether-linked A (14), toB (the15) andglycerol-1-phosphate napyradiomycin D1 (backbone16). [26,27]. that meroterpenoid 16 (Figure5) exhibited signiﬁcant inhibitory activity against methicillin-resistant The chemical structure and variety of archaeal lipids provide the necessary stability under extreme Staphylococcus aureus Mycobacterium tuberculosis HepG2 environmentalAnother uniqueconditions,, natural as source many ofarchaea macrocyclic thriveand meroterpenoids in such. conditions, is archaeal including lipids consistinghigh or low of temperatures,methylatedAnother isoprenoid uniquehigh salinity, natural chains, and source whic extremeh of are macrocyclic acidicether-linked or alkaline meroterpenoids to the pH glycerol-1-phosphate values. is Recently, archaeal higher lipids backbone consistinghomologues [26,27]. of methylatedThe chemical isoprenoid structure chains,and variety which of arearchaeal ether-linked lipids provide to the glycerol-1-phosphate the necessary stability backbone under extreme[26,27 ]. environmental conditions, as many archaea thrive in such conditions, including high or low temperatures, high salinity, and extreme acidic or alkaline pH values. Recently, higher homologues

Plants 2020, 9, 1582 5 of 26

The chemical structure and variety of archaeal lipids provide the necessary stability under extreme environmentalPlants 2020, 9, x FOR conditions, PEER REVIEW as many archaea thrive in such conditions, including high or5 of low 27 temperatures, high salinity, and extreme acidic or alkaline pH values. Recently, higher homologues of the widelywidely knownknown macrocyclicmacrocyclic isoprenoidisoprenoid lipidlipid nucleinuclei CC8686,, containingcontaining 0–60-6 cyclopentyl rings in (hyper) thermophilic archaea, have been identified identified [28], [28], which accounts for up to 21% of the total amount of of tetraether tetraether lipids lipids in in cells. cells. Tandem Tandem liqu liquidid chromatography-mass-spectrometry chromatography-mass-spectrometry confirms confirms that thatthe additional the additional carbon carbon atoms atoms in the in C the87-88 C homologues87–88 homologues are located are located in the in esterified the esterified chains. chains. The Thestructures structures identified identified include include dialkyl dialkyl and and monoalkyl monoalkyl ("H-shaped") (“H-shaped”) tetraesters tetraesters containing containing C40-42 C40–42 or Cor81- C82 81–82hydrocarbons,hydrocarbons, respectively, respectively, many many of which of which are new are new compounds. compounds. Recent studies have shown [[29]29] that macrocyclicmacrocyclic meroterpenoid polyketides produced by Bacillus and Paenibacillus species can be used as antimicrobial agents to combat outbreaks of phytopathogenic diseases, as wellwell asas multidrug-resistantmultidrug-resistant humanhuman pathogens.pathogens. Among them are didifficidinfficidin (17), paenimacrolidinpaenimacrolidin (18), andand macrolactinmacrolactin ((1919)) (Figure(Figure6 ).6). DiDifficidinfficidin ( (1717)) is is a highly unsaturated macrocyclic polyene, consisting of a 22-membered carbon skeleton with a phosphatephosphate group. Although Although difficidin difficidin is is primarily known for its activity against human pathogens, it is also eeffectiveffective against plant diseases caused by ErwiniaErwinia amylovoraamylovora and PectobacteriumPectobacterium carotovorum, as wellwell as XanthomonasXanthomonas oryzae oryzae. .Macrolactins Macrolactins are are a class a class of over of over 30 different 30 different 24-membered 24-membered macrolactones macrolactones with withthree threediene diene moieties moieties in the in thecarbon carbon backbone, backbone, isol isolatedated from from various various bacterial bacterial sources, sources, including Bacillus species such as B. subtilis and B. amyloliquefaciens . Recently, Recently, a a new new derivative derivative of of macrolactins, macrolactins, macrolactin AA ( 19(19),), was was isolated isolated from from the theBacillus Bacillus subtilis subtilis B5 bacterial B5 bacterial strain. strain. Bacillus Bacillus macrolactins macrolactins exhibit antimicrobialexhibit antimicrobial activity activity against against gram-negative gram-negative and gram-positive and gram-positive bacteria, bacteria, including including MRSA MRSA and VRE, and asVRE, well as as antiviralwell as activityantiviral against activity Herpes against simplex Herpes and HIVsimplex in lymphoblastic and HIV in cells.lymphoblastic Paenimacrolidin cells. (Paenimacrolidin18) is a secondary (18 metabolite) is a secondary of Paenibacillus metabolitesp. F6-B70of Paenibacillus. It exhibited sp. mainlyF6-B70. bacteriostatic It exhibited activitymainly andbacteriostatic exhibited activity antimicrobial and exhibited activity antimicrobial against the pair activity of MRSA against strains the pair tested of MRSA and ampicillin strains tested resistant and Staphylococcusampicillin resistant epidermidis Staphylococcus. epidermidis.

Figure 6. Structures of polyketides 17-20.

Interestingly, macrocyclicmacrocyclic polyketide polyketide (20 ) (Figure(20) (Figure6) showed 6) [showed30] significantly [30] significantly stronger antioxidant stronger andantioxidant anti-inflammatory and anti-inflammatory properties compared properties to comp someared commercially to some commercially available antioxidant available agents antioxidant and is aagents candidate and foris a preventing candidate food for spoilagepreventing and food inflammatory spoilage diseasesand inflammatory caused by oxidativediseases stress.caused by oxidativeIt should stress. be noted that the majority of natural meroterpenoids obtained during enzyme-mediated cascadeIt should reactions be ofnoted coupled that biosynthesis, the majority although of natural they meroterpenoids are macrocyclic compounds,obtained during do not enzyme- exhibit “classical”mediated cascade supramolecular reactions properties. of coupled They biosynthesis are important, although secondary they metabolites are macrocyclic in various compounds, biochemical do processesnot exhibit and "classical" many of themsupramolecular have a suffi cientlyproperties high. biologicalThey are activity,important which secondary makes themmetabolites promising in drugvarious candidates biochemical [1]. However,processes amongand many the naturalof them macrocyclichave a sufficiently meroterpenoids, high biological a class activity, of compounds which makes them promising drug candidates [1]. However, among the natural macrocyclic meroterpenoids, a class of compounds with the properties of supramolecular systems can be distinguished. These are the prenylated bacterial nonribosomal lipopeptides [31], which represent the smallest group of isoprenoids of conjugated biosynthesis but have been actively studied in recent

Plants 2020, 9, 1582 6 of 26 with the properties of supramolecular systems can be distinguished. These are the prenylated bacterial nonribosomal lipopeptides [31], which represent the smallest group of isoprenoids of conjugated Plants 2020, 9, x FOR PEER REVIEW 6 of 27 biosynthesis but have been actively studied in recent decades. The study of prenylated macrocyclic peptidesdecades. asThe allosteric study of activators prenylated of chambermacrocyclic bacterial peptides proteases as allosteric made itactivators possible toof placechamber them bacterial among potentialproteases antibiotics.made it possible The ﬁrst to place representatives them among of thispotent classial ofantibiotics. compounds The are first acyldepsipeptides representatives of21 this–23 (Figureclass of7 compounds)[15,29,32]. are acyldepsipeptides 21-23 (Figure 7) [15,29,32].

Figure 7.7. Structures of acyldepsipeptides 2121–-23..

Since the structure and composition of nonribosomal lipopeptides are not limited or determined by theSince genetic the structure code, they and may composition contain nonproteinogenicof nonribosomal lipopeptides (ornithine, are homoserine, not limitedβ or-amino determined acids) andby the modified genetic aminocode, they acids may (hydroxylated, contain nonproteinogenic chlorinated, N-methylated(ornithine, homoserine, or glycosylated) β-amino in acids) the L- and or D-configurations.modified amino acids The fatty(hydroxylated, acid moiety chlorinated, can be composed N-methylated of a linear, or cyclic, glycosylated) or branched in the terpene L- or tail,D- theconfigurations. length of which The canfatty vary acid (typically moiety can C6-C be18 composed) and contain of a functional linear, cyclic, groups or branched (e.g., hydroxyl terpene or tail, amino). the Alength macrocyclic of which ring canof vary nonribosomal (typically C prenylated6-C18) and contain lipopeptides functional is formed groups between (e.g., hydroxyl the C-terminus or amino). of theA macrocyclic peptide and ring the of hydroxyl, nonribosomal phenolic, prenylated or amine li functionalpopeptides groups is formed that between belong to the either C-terminus the amino of acidthe peptide side chain and or the the hydroxyl, terpene moiety. phenol Theic, or resulting amine functional macrolactones groups or macrolactamsthat belong to dieitherffer in the ring amino size, whichacid side ranges chain from or the 4 toterpene 16 amino moiety. acids The [15 resulting]. macrolactones or macrolactams differ in ring size, whichMany ranges nonribosomal from 4 to 16 prenylatedamino acids lipopeptides [15]. have amphiphilic properties, which make them usefulMany as eff ectivenonribosomal biosurfactants prenylated [33]. Theylipopeptides influence have biofilm amphiphilic formation orproperties, degradation which by changing make them the surfaceuseful as tension effective of thebiosurfactants environment. [33]. Nonribosomal They influence prenylated biofilm lipopeptidesformation or also degradation have membranotropic by changing properties.the surface Intension addition, of the they environment. have the ability Nonr toibosomal formsupramolecular prenylated lipopeptides associates containingalso have water-insolublemembranotropic nutrients properties. to facilitate In addition, the transport they have of thethe latterability into to theform cells su [pramolecular34]. associates containingThus, thewater-insoluble number of detected nutrients representatives to facilitate the of naturaltransport macrocyclic of the latter meroterpenoids into the cells [34]. is increasing eachThus, year. Thisthe isnumber primarily of duedetected to the establishmentrepresentative ofs biochemicalof natural macrocyclic mechanisms meroterpenoids of the formation ofis meroterpenoidsincreasing each year. in the This course is primarily of metabolism. due to Suchthe establishment identified biosynthetic of biochemical pathways mechanisms open up of new the perspectivesformation of inmeroterpenoids the discovery of in previously the course unknown of metabolism. representatives Such identified of macrocyclic biosynthetic meroterpenoids. pathways Extensionopen up new of aperspectives number of macrocyclicin the discovery meroterpenoids of previously will unknown make it representatives possible to finally of macrocyclic consolidate thismeroterpenoids. class of compounds Extension in aof number a number of of macromolecules. macrocyclic meroterpenoids Initially nontoxic, will make biodegradable, it possible availableto finally meroterpenoidsconsolidate this withclass a macrocyclicof compounds cavity in can a replacenumber or beof anmacromolecules alternative to. classical Initially macrocyclic nontoxic, platforms,biodegradable, which availa usuallyble meroterpenoids exhibit high toxicity. with a macrocyclic The disadvantages cavity can of replace using naturalor be an macrocyclic alternative meroterpenoidsto classical macrocyclic include platforms, relatively which low yields usually of target exhibit products high toxicity. during The their disadvantages disengagement of using from natural macrocyclic meroterpenoids include relatively low yields of target products during their disengagement from biomass. This imposes serious restrictions on the use of natural meroterpenoids. However, the development of semisynthetic production methods resolves these restrictions.

3. Synthetic Macrocyclic Meroterpenoids

Plants 2020, 9, 1582 7 of 26 biomass. This imposes serious restrictions on the use of natural meroterpenoids. However, the development of semisynthetic production methods resolves these restrictions.

Plants3. Synthetic 2020, 9, x FOR Macrocyclic PEER REVIEW Meroterpenoids 7 of 27

Synthetic macrocyclicmacrocyclic meroterpenoids meroterpenoids are obtainedare obtained by combining by combining “classic” “classic” macrocyclic macrocyclic platforms, platforms,such as cyclodextins such as cyclodextins or meta- and or paracyclophanes,meta- and paracyclophanes, with various with kinds vari ofous terpenoid kinds fragmentsof terpenoid or fragmentsthrough macrocyclization or through macrocyclization of several terpene of several derivatives terpene [4 derivatives]. [4]. In this this regard regard the the most most studied studied synthon synthon for for macrocyclization macrocyclization is the is thetriterpene triterpene steroid steroid framework. framework. The steroidThe steroid core coreis one is of one the of largest the largest and most and most conformati conformationallyonally rigid rigidreadily readily available available terpene terpene molecules molecules with axialwith or axial equatorial or equatorial substitution substitution patterns patterns available, available, occurring occurring in a homochiral in a homochiral form. Moreover, form. because Moreover, of thebecause importance of the of importance steroids in of biochemistry steroids in biochemistryand medicine, andsteroids medicine, have been steroids studied have in beengreat studieddetail [35]. in Considerationgreat detail [35 of]. Considerationmacrocyclic meroterpenoids of macrocyclic meroterpenoidsshould start with should cholaphanes start with and cholaphanes cyclocholates. and Cholaphanescyclocholates. are Cholaphanes bile acid macrocycles are bile acid composed macrocycles of two composed to four of steroid two to subunits four steroid linked subunits together linked by differenttogether groups by different of atoms groups as spacers. of atoms Macrocyclic as spacers. ch Macrocyclicolaphanes, cholaphanes,consisting of two consisting steroidof fragments, two steroid in contrastfragments, to their in contrast acyclic toanalogs, their acyclic tend to analogs, form ho tendst–guest to form complexes host–guest [35]. complexesCyclocholates [35]. are Cyclocholates macrocyclic polyestersare macrocyclic formed polyesters by macrocyclization formed by of macrocyclization cholic acid derivatives of cholic [36]. acid derivatives [36]. Davis was was the the first first to to report report the the synthesis synthesis of of a acyclic cyclic dimer dimer of of cholic cholic acid acid in in1989 1989 [37]. [37 As]. As part part of thisof this work, work, macrocycle macrocycle 2727, containing, containing two two cholic cholic acid acid fragment fragmentss linked linked by by a a rigid rigid para-substituted benzyl bridge, was synthesized. The The introduction introduction of a a conformationally conformationally rigid bridge made it possible to avoid excessive flexibility flexibility of the skeleton (Scheme1 1))[ [37].37].

Scheme 1. 1. ReagentsReagents and and conditions: conditions: i, (Me i,3Si) (Me2NCH3Si)22-NCHp-C6H24--Li,p-C MnI6H4-Li,2, Et2 MnIO; ii,2 ,(CF Et32CO)O; ii,2O, (CFCF3COOH;CO)2O, iii,CF (CF3COOH;3SO2)2O, iii, 2,6-di-t-butyl-4-met (CF3SO2)2O, 2,6-di-t-butyl-4-methylpyridine;hylpyridine; iv, (Me3Si)2NCH2-p-C iv,6H (Me4-ZnBr,3Si) 2Pd(PPhNCH2-3p)4-C, THF,6H4-ZnBr, Et2O; v,Pd(PPh H2, Pd/C;3)4, THF, vi, NaOH, Et2O; v,MeOH, H2, Pd THF;/C; vi, vii. NaOH, (EtO) MeOH,2POCN. THF; CHCl vii.3, DMF, (EtO) 2KPOCN.2HPO4; CHClviii, (BOC)3, DMF,2O, K DIPEA,2HPO4; THF;viii, (BOC) ix, DCC,O, C DIPEA,6F5OH; THF;x. CF3 ix,COOH; DCC, xi, C DMAPF OH;∙HOOCCF x. CF COOH;3, CHCl xi,3, DMAPDMF, KHOOCCF2HPO4. , CHCl , DMF, 2 6 5 3 · 3 3 K2HPO4. Currently, сholaphanes are an actively studied class of macrocycles. Recently a group led by Ju developed [38] and synthesized a new macrocyclic sensor, 31, (Scheme 2) consisting of cholesterol, binaphthalene and 1,2,3-triazole fragments. Macrocyclization was carried out by azizide-alkyne cycloaddition between azide 28 and alkyne derivative 30, obtained by alkylation of 29 with propargyl bromide. Fragments of the triterpenoid play the role of a chiral framework, the binaphthyl fragment acts as a fluorophore fragment, and the 1,2,3-triazole fragment plays the role of a coordination center [38].

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Currently, cholaphanes are an actively studied class of macrocycles. Recently a group led by Ju developed [38] and synthesized a new macrocyclic sensor, 31, (Scheme2) consisting of cholesterol, binaphthalene and 1,2,3-triazole fragments. Macrocyclization was carried out by azizide-alkyne cycloaddition between azide 28 and alkyne derivative 30, obtained by alkylation of 29 with propargyl bromide. Fragments of the triterpenoid play the role of a chiral framework, the binaphthyl fragment acts Plantsas a ﬂuorophore 2020,, 9,, xx FORFOR fragment,PEERPEER REVIEWREVIEW and the 1,2,3-triazole fragment plays the role of a coordination center8 [of38 27].

O O O O O O O O O O O O

N3 N3 N N N N 3 3 ii 28 N N

O O O O OH i O O OH

29 29 31 (53%) 30 (55%) 30 (55%)

Scheme 2.2. Reagents and conditions:conditions: i, propargyl bromide, Cs2CO3,, DMF, DMF, rt, 1212 h;h; ii,ii, CuSOCuSO4∙5H2O,O, 2 3 4· 2 sodium l-ascorbate, t-BuOH:THF:H2O = 5:1:15:1:1 (volume (volume ratio), ratio), 65 65◦C,C, 8 8 h. h. 2 ◦ The authors have shown [38] [38] that macrocycle 31 can serve as an “on-off” “on-oﬀ” fluorescent ﬂuorescent molecular 2+ sensor for the HgHg2+ ionion due due to to the the 1,2,3-triazole 1,2,3-triazole fragment fragment introduced introduced as as a a result result of of the CuAAC click 2+ reaction. This This complex complex [ [3131∙HgHg2+] ]can can be be used used in in the the cascade cascade recognition recognition of of amino amino acids with high reaction. This complex [31∙·Hg ] can be used in the cascade recognition of amino acids with high enantioselectivity (Figure8 8).).

2+ Figure 8. Schematic representationrepresentation of of the the recognition recognition behavior behavior of of31 31for for Hg Hgion2+ion and and its its applications applications in incascade cascade enantioselective enantioselective recognition recognition of aminoof amino acids. acids. The group led by Pandey reported [39] the eﬃcient synthesis of a bis-1,2,3-triazolium cholaphane The group led by Pandey reported [39] the efficient synthesis of a bis-1,2,3-triazolium macrocycle based on bile acid via the click reaction (Scheme3) and the use of the product, 38, cholaphane macrocycle based on bile acid via the click reaction (Scheme 3) and the use of the product, to recognize the chloride ion. The propargyl derivative of methyldeoxycholate, 33, was synthesized 38, to recognize the chloride ion. The propargyl derivative of methyldeoxycholate, 33, was by the reaction of deoxycholic acid 32 with propargyl bromide in the presence of sodium hydride in synthesized by the reaction of deoxycholic acid 32 with propargyl bromide in the presence of sodium THF followed by the addition of MeOH-H2SO4. Monobromoacetyl derivative 34 was prepared by hydride in THF followed by the addition of MeOH-H2SO4. Monobromoacetyl derivative 34 was reacting propargyl ether 33 with bromoacetyl bromide in the presence of K2CO3 in trichloromethane. prepared by reacting propargyl ether 33 with bromoacetyl bromide in the presence of K2CO3 in Compound 34 upon treatment with sodium azide in DMF gives precursor 35, which in the presence trichloromethane. Compound 34 upon treatment with sodium azide in DMF gives precursor 35, which in the presence of CuSO4 (10 mol %) and sodium ascorbate (20 mol %) gives cholaphane 36 based on triterpene bile acid in 50% yield. Cholaphane 36 was methylated at the nitrogen of the triazole moieties with methyl iodide to give compound 37. The PF6-salt 38 was obtained by ion exchange of the iodide salt of 37 with NH4PF6 in MeOH [39].

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of CuSO4 (10 mol %) and sodium ascorbate (20 mol %) gives cholaphane 36 based on triterpene bile acid in 50% yield. Cholaphane 36 was methylated at the nitrogen of the triazole moieties with methyl iodide to give compound 37. The PF6-salt 38 was obtained by ion exchange of the iodide salt of 37 with NHPlants4PF 20206 ,in 9, MeOHx FOR PEER [39 ].REVIEW 9 of 27

Scheme 3. Reagents and conditions: i, THF, NaH, PropargylPropargyl Bromide, 5050 ◦°C,C, 24 h;h; ii,ii, MeOH,MeOH, HH22SO4,, reﬂux;reflux; iii,iii, CHClCHCl33,K, K2CO3,, 0-5 0–5 °C,◦C, BrCH BrCH22COBr,COBr, 2 2 h; h; iv, iv, DMF, DMF, NaN3,, 50 50 °C,◦C, 12 h; v, CuSO44∙5H2O, Sodium · ascorbate, t-BuOH–H2O (10:1), 80 °C,◦C, 72 72 h; h; vi, vi, CHCl CHCl33, ,MeI, MeI, 72 72 h; h; vii, vii, MeOH, MeOH, NH NH44PFPF6.6 .

1 The receptor properties of compound 38 were studiedstudied byby 1H NMR spectroscopy by adding tetrabutylammonium salts salts to a solution of receptorreceptor 3838 inin CDClCDCl33. Upon Upon addition addition of of aliquots of the solution ofof BuBu44NXNX (X(X= =F F−−,, ClCl−−, BrBr−-,,I I−−, ,CH CH33COOCOO-,− H,H2PO2PO4−)4 −to) toa asolution solution of of 3838, ,significant significant downfield downfield shifts were observed for the triazolium groups sugg suggestingesting the interaction of the anion with triazolium + by forming C+ -H-X hydrogen bonds. In addition, noticeable downfield shifts were also observed for by forming C -H-X−−hydrogen bonds. In addition, noticeable downfield shifts were also observed for one of the methylene protons of both acetyl groups,groups, which indicatesindicates their participation in forming hydrogen bonds with anions [[39].39]. The stoichio stoichiometrymetry in all studied cases was 1:1.1:1. Receptor 38 was 1 found to bebe highlyhighly selectiveselective forfor chloridechloride withwith aa binding binding constant constant K Ka a= = 37003700 MM−-1.. The The strength strength of the interaction decreased decreased in in the the order: order: Cl Cl− −> HSO> HSO4− >4 −H>2POH24-PO > F4−− >> BrF−− > >CHBr3−COO> CH− >3 ICOO−. The− high> I− .selectivity The high selectivityof this receptor of this with receptor respect with to respect the chloride to the chlorideion was ionexplained was explained by the authors by the authors as being as due being to duethe tocorresponding the corresponding size of sizethe receptor of the receptor cavity, which cavity, provides which provides the most the effective most e bindingffective bindingwith the withchloride the chlorideanion. Consequently, anion. Consequently, this system this may system be an may attractive be an attractive carrier for carrier chloride for chlorideions. Carriers ions. of Carriers chloride of chlorideions have ions direct have medical direct medical use in usethe in treatment the treatment of cystic of cystic fibrosis fibrosis and and other other diseases diseases caused caused by insuinsufficientfficient transport of chloridechloride ionsions acrossacross biologicalbiological membranesmembranes [[40].40]. A group of Polish scientists [41] [41] reported the preparation of new dimeric cholaphanes 44 and 45 with disulfide disulfide spacers (Scheme (Scheme 44).). The The synthetic synthetic rout routee consisted consisted in in a aseries series of of successive successive reactions reactions of ofthe the conversion conversion of ofcholic cholic acid acid ester ester 3939 intointo alcohol alcohol 4040, ,followed followed by by the the substitution substitution of of two alcoholalcohol groups by the Appel reaction. Then the precursor 41 was converted to diisocyanate 42, which was reduced to the correspondingcorresponding dithiol 43. Then, Then, macrocycles macrocycles 4444 and 45 were obtained by oxidative macrocyclization to give 43. Disulfide spacers link two identical steroid subunits head-to-head, to give cis-dimer 45, or head-to-tail to give trans-dimer 44. Another cyclic dimer, 48, was also obtained (Scheme 5), containing both disulfide and sulfide spacers in its structure. Cholaphanes 44 and 45 can be potentially useful for molecular or ionic recognition [41].

Plants 2020, 9, 1582 10 of 26 Plants 2020, 9, x FOR PEER REVIEW 10 of 27 macrocyclization to give 43. Disulfide spacers link two identical steroid subunits head-to-head, to give cis-dimer 45, or head-to-tail to give trans-dimer 44. Another cyclic dimer, 48, was also obtained (Scheme5), containing both disulfide and sulfide spacers in its structure. Cholaphanes 44 and 45 can bePlants potentially 2020, 9, x FOR useful PEER for REVIEW molecular or ionic recognition [41]. 10 of 27

Scheme 4. Reagents and conditions: i, THF, LiAlH4; ii, I2, TPP, Py, C6H6; iii, KSCN, Me2CO; iv, THF,

LiAlH4; v, I2, NaOH, THF, H2O.

An attempt was also made to selectively obtain isomer 45 directly from the acyclic disulfide dimer. The “cis-dimer” 45 was finally obtained from acyclic disulfide 46 and, during this reaction, cholaphane 48 with a sulfide linker was also formed (Scheme 5). The latter was also selectively SchemeScheme 4. 4.Reagents Reagents andand conditions:conditions: i, THF, LiAlH4;; ii, ii, I I22, ,TPP, TPP, Py, Py, C C66HH66; ;iii, iii, KSCN, KSCN, Me Me2CO;2CO; iv, iv, THF, THF, 2 formedLiAlHLiAlH by4 using4;; v,v, I 2I2,, NaOH,aNaOH, large THF,THF,excess HH2 2ofO. NaSH∙2H O in the reaction with diiodide 47 [41].

Scheme 5. Reagents and conditions: i, I , TPP, Py, C H ; ii NaSH 2H O, EtOH. Scheme 5. Reagents and conditions: i, I22, TPP, Py, C66H66; ii NaSH∙·2H2O, EtOH.

AnCyclocholates-macrocyclic attempt was also made topolyesters selectively of obtain cholic isomer acid 45weredirectly first fromdescribed the acyclic by Bonar-Law disulfide dimer. [36]. TheCyclocholates “cis-dimer” 50a–e45 was were finally obtained obtained by froma Yamaguchi acyclic disulfide macrolactonization46 and, during from this monomeric reaction, cholaphane hydroxy

48acidswith 49a–e a sulfide using linker 2,6-dichlorobenzoylchloride was also formed (Scheme as5 coupling). The latter reagent was alsoin a selectivelyone-pot synthesis formed (Scheme by using 6). a large excess of NaSHScheme2H 5. OReagents in the reactionand conditions: with diiodidei, I2, TPP, Py,47 [C416H].6; ii NaSH∙2H2O, EtOH. The resulting mixture· of2 cyclic compounds was separated by flash chromatography. The individual yieldsCyclocholates-macrocyclic of target cyclooligomers are polyesters shown in of Table cholic 1 [36]. acid were first described by Bonar-Law [36]. CyclocholatesCyclocholates-macrocyclic50a–e were obtained polyesters by a Yamaguchi of cholic acid macrolactonization were first described from monomericby Bonar-Law hydroxy [36]. acidsCyclocholates49a–e using 50a–e 2,6-dichlorobenzoylchloride were obtained by a Yamaguchi as coupling macrolactonization reagent in a one-pot from monomeric synthesis (Scheme hydroxy6). Theacids resulting 49a–e using mixture 2,6-dichlorobenzoylchloride of cyclic compounds was as separated coupling reagent by flash in chromatography. a one-pot synthesis The (Scheme individual 6). yieldsThe resulting of target mixture cyclooligomers of cyclic arecompounds shown in was Table separated1[36]. by flash chromatography. The individual yields of target cyclooligomers are shown in Table 1 [36].

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Scheme 6. Reagents and conditions: i, 2,6-dichlorobenzoyl chloride, DMAP, toluene, 100 °C.

Scheme 6. Reagents and conditions: i, 2,6-dichlorobenzoyl chloride, DMAP, toluene,toluene, 100100 ◦°C.C. Table 1. Yields of functionalized cyclocholates 50a-e (n = ring size) a Table 1. Yields of functionalized cyclocholates 50a-e (n = ring size) a a TableR 1 1. YieldsR 2 of functionalized Cmonomer cyclocholates b n = 2 50a-e 3 (n = ring 4 size) 5 6 1 2 b R R Cmonomer n = 2 3 4 5 6 49a RH 1 RH 2 50a C10.0monomer mM b n 1.5 = 2 3.0 3 <1 4 <1 5 <1 6 c 49a 49b49a HHH TFAH 50a50b50a 10.02.0 mM mMmM (11) 1.5 1.5 (47) 3.0 3.0 (14) <1 <1 (5) <1 <(4) <11 <1 49b H TFA 50b 2.0 mM (11)c (47) (14) (5) (4) 49c TFA TFA 50c 2.0 mM 0 c 41(53) 8(15) 4(6) 1(5) 49c 49bTFA H TFA TFA 50c50b 2.0 mMmM (11) 0 (47) 41(53) (14)8(15) (5) 4(6)(4) 1(5) 49d MEM MEM 50d 4.0 mM 0 39 13 ndd nd 49d 49cMEM TFA MEM TFA 50d50c 2.04.0 mMmM 0 0 41(53) 39 8(15) 134(6) nd1(5)d nd 49e 49d49eMEEAc MEEAcMEM MEEAc MEEAcMEM 50e 50d50e 2.54.0 mMmM 0 0 2239 22 1213 12 nd ndd nd nd nd (a) TFA = Trifluoroacetate. MEM = 2-(methoxyethoxy)methyl ether. MEEAc = a TFA = Trifluoroacetate.49e MEEAc MEMMEEAc= 2-(methoxyethoxy)methyl 50e 2.5 mM ether. 0 MEEAc 22= 2(methcoxyethoxy)ethoxyacetate; 12 nd nd b c 19 19 2(methcoxyethoxy)ethoxyaceta(a)Initial TFA monomer = concentration;Trifluoroacetate.te; (b)Yields InitialMEM in monomer brackets = determined2-(methoxyethoxy)methyl concentration;F spectrum(c) Yields ofin brackets crudeether. reaction determinedMEEAc mixtures; F= d Not determined. spectrum2(methcoxyethoxy)ethoxyaceta of crude reaction mixtures;te; (b) (d)Initial Not monomer determined. concentration; (c) Yields in brackets determined 19F spectrum of crude reaction mixtures; (d) Not determined. The dependencedependence of of the the macrocycle macrocycle size size on on the the initial initial monomer monomer concentration concentration was established was established using 19 19 usingF NMRThe F NMRdependence spectroscopy spectroscopy of for the trifluoroacetate-protected formacrocycle trifluoroacetate-protected size on the cyclocholates, initial cyclocholates, monomer since concentration the since fluorine the fluorine resonance was established resonance turned outturnedusing to 19 be Fout NMR a sensitiveto bespectroscopy a sensitive indicator for ofindicator trifluoroacetate-protected the chemical of the environment. chemical environment. cyclocholates, The relatively The since high relatively the yields fluorine ofhigh cyclotrimers resonance yields of (Tablecyclotrimersturned1 )out make to (Table thisbe a particular sensitive1) make seriesindicatorthis particular of cyclooligomers of the series chemical of (Figure cyclooligomers environment.9) available The(Figure in gramrelatively 9) quantities available high withoutyieldsin gram of thequantitiescyclotrimers need for without high(Table dilution the 1) needmake [36 for ].this high particular dilution [36].series of cyclooligomers (Figure 9) available in gram quantities without the need for high dilution [36].

Figure 9.9. Spatial structure of tricyclic cyclocholates (see(see RR11 and R 2 atat Table Table 11).). Figure 9. Spatial structure of tricyclic cyclocholates (see R1 and R2 at Table 1). It was also found that the sizesize ofof thethe macrocyclemacrocycle formedformed dependeddepended on thethe naturenature ofof thethe substituentssubstituents on the axial hydroxyl groups. It should be noted that polyester chains facilitate the formation on theIt axialwas alsohydroxyl found groups. that the It size shou ofld the be macrocycle noted that polyesformedter depended chains facilitate on the naturethe formation of the substituents of not only of not only cyclotrimers but also larger macrocycles. The authors note that cyclocholates, in this cyclotrimerson the axial hydroxyl but also larger groups. macrocycles. It should be The noted authors that nopolyeste thatter cyclocholates, chains facilitate in thethis formationwork, are consideredof not only work, are considered as semirigid macrocyclic lactones, built from large units carrying convergent ascyclotrimers semirigid butmacrocyclic also larger lactones, macrocycles. built Thefrom authors large nounitste that carrying cyclocholates, convergent in this functionality, work, are considered and they functionality, and they represent a universal type of receptor architecture. However, quantum-chemical representas semirigid a universal macrocyclic type lactones,of receptor built architecture. from large However, units carrying quantum-chemical convergent calculationsfunctionality, [42] and using they a calculations [42] using a nonfunctionalized cyclotrimer 50a show that the current generation of represent a universal type of receptor architecture. However, quantum-chemical calculations [42] using a cyclocholates is too ﬂexible to be used as macrocyclic receptors in molecular recognition [37].

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Plants 2020, 9, 1582 12 of 26 nonfunctionalized cyclotrimer 50a show that the current generation of cyclocholates is too flexible to be used as macrocyclic receptors in molecular recognition [37]. Gao and Dias Dias [43] [43] reported reported the the synthesis synthesis of of seve sevenn macrocyclic macrocyclic bile bile acid acid oligomers oligomers (Scheme (Scheme 7).7 In). Inthis this work, work, as asin inthe the previous previous one, one, the the Yamaguchi Yamaguchi method method was was used used and and the the yields yields of of 52a–f varied from 3 to 45% (Table 2 2).). CyclomonomerCyclomonomer 52g and macrocyclic dimer 52f were obtained only as a result of the cyclization reaction of 7-deoxycholic7-deoxycholic acid. Under Yamaguchi reaction conditions, cholic acid derivatives givegive mainlymainly macrocyclic macrocyclic trimeric trimeric products products52a,b,e, 52a,b,e,while while 24-norcholic 24-norcholic acid acid derivatives derivatives give mainlygive mainly macrocyclic macrocyclic tetrameric tetrameric products products52c [ 4352c]. [43].

Scheme 7. Reagents and conditions: i, i, 2,6dichlorobenzoyl 2,6dichlorobenzoyl chlori chloride,de, DMAP, toluene, 12 h.

Table 2. Yields of functionalized cyclocholates 52a–e (m = ring size). Table 2. Yields of functionalized cyclocholates 52a–e (m = ring size). 1 2 CompoundCompound RR1 R R2 mm n n Yield (%) Yield (%) 51a 51a OAc OAcOAc –– 22 – – 51b 51b OAc OAcOAc –– 11 – – 51c H OAc – 2 – 51c 52a OAcH OAcOAc 3– 22 45 – 52a 52b OAc OAcOAc 33 12 15 45 52b 52c OAc OAcOAc 43 11 42 15 52c 52d OAcH OAcOAc 24 21 3.5 42 52e 52d H OAcOAc 32 22 41 3.5 52f H OH 2 2 4.2 52e H OAc 3 2 41 52g H OCO− – 2 32 52f H OH 2 2 4.2 52g H OCO- – 2 32 It should be noted that there are far fewer papers devoted to cyclocholates than there are related to cholaphanes.It should Thisbe noted lack ofthat interest there inare cyclocholates far fewer papers may devoted be due to to the cyclocholates absence of potentialthan there coordination are related centersto cholaphanes. in their structure, This lack in of contrast interest to thein cyclocholates related cholaphanes, may be which due containto the absence functional of groupspotential of dicoordinationﬀerent nature centers that can in acttheir as coordinationstructure, in centers. contrast to the related cholaphanes, which contain functionalSyntheses groups of macrocyclicof different nature dimers th containingat can act as terpene coordination fragments centers. other than cholesterol are also poorlySyntheses presented of macrocyclic in the literature. dimers In containing one example, terpene a group fragments of scientists other than from cholesterol Novosibirsk are also [44] synthesizedpoorly presented macrocyclic in the meroterpenoidsliterature. In one56, 57exampland 61e, bya group cyclization. of scientists The authors from proposedNovosibirsk a simple [44] α andsynthesized eﬀective macrocyclic method for meroterpenoids the synthesis of 56 bis-, 57 and-sulfanyloximes 61 by cyclization.54, 55 Theand authors59, 60 proposedfrom unsaturated a simple monoterpene hydrocarbons, such as (+)-3-carene and ( )-α-pinene, previously converted into the and effective method for the synthesis of bis-α-sulfanyloximes− 54, 55 and 59, 60 from unsaturated correspondingmonoterpene hydrocarbons, nitrosochlorides such53, 58as (Schemes(+)-3-carene8 and and9). (-)-α-pinene, previously converted into the corresponding nitrosochlorides 53, 58 (Schemes 8 and 9).

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Scheme 8. Reagents and conditions: i, NOCl2; ii, NaS(CH2)2SNa; iii, KS(CH2)3SK, iv, CH2Cl2. SchemeScheme 8. 8.Reagents Reagents and and conditions: conditions: i,i, NOClNOCl22;; ii,ii, NaS(CHNaS(CH22))22SNa; iii, KS(CH 2))33SK,SK, iv, iv, CH CH22ClCl2.2 .

SchemeScheme 9. 9.Reagents Reagents and and conditions: conditions: i,i, NOClNOCl22;; ii,ii, NaS(CHNaS(CH22)2SNa; iii, KS(CH 2))33SK,SK, iv, iv, CH CH22ClCl2.2 . Scheme 9. Reagents and conditions: i, NOCl2; ii, NaS(CH2)2SNa; iii, KS(CH2)3SK, iv, CH2Cl2. The reaction of dimeric nitrosochloride 53 or 58 with a solution of the dithiolate in anhydrous The reaction of dimeric nitrosochloride 53 or 58 with a solution of the dithiolate in anhydrous methanol under an inert gas atmosphere led to the corresponding bis-α sulfanyloximes 54, 55, 59 and methanol under an inert gas atmosphere led to the corresponding bis-α sulfanyloximes 54, 55, 59 and 60 (Schemes 88 and and9 ).9). The The maximum maximum yields yields of of 1,2-dithiol 1,2-dithiol derivatives derivatives 54 and 59 were achieved using 60 (Schemes+ 8 and 9). The maximum yields of 1,2-dithiol derivatives+ 54 and 59 were achieved using Na+ as a counter ion, while for 1,3-dithiol derivatives 55 and 60 K + was more successful. The authors Na+ as a counter ion, while for 1,3-dithiol derivatives 55 and 60 K+ was more successful. The authors explain this by the template eﬀect of the alkali metal cation, which is similar to that observed during explain this by the template effect of the alkali metal cation, which is similar to that observed during the formation of crown ethers. The cyclization of bis-α-sulfanyloximes 54, 55, 59, and 60 had been the formation of crown ethers. The cyclization of bis-α-sulfanyloximes 54, 55, 59, and 60 had been carried out by bonding hydroxyl groups with dichloromethane under conditions of phase transfer carried out by bonding hydroxyl groups with dichloromethane under conditions of phase transfer catalysis. It is likely that macrocyclization follows the generally accepted mechanism of ether formation catalysis. It is likely that macrocyclization follows the generally accepted mechanism of ether under conditions of phase transfer catalysis. In the case of compound 60, the target macrocycle 62 formation under conditions of phase transfer catalysis. In the case of compound 60, the target was not obtained; the reaction resulted in the formation of a very complex mixture of oligomerization macrocycle 62 was not obtained; the reaction resulted in the formation of a very complex mixture of products [44]. oligomerization products [44]. The group of Kataev [45] synthesized a number of macrocyclic glycoterpenoids. As a basis for The group of Kataev [45] synthesized a number of macrocyclic glycoterpenoids. As a basis for creating macrocycles, diterpenoid isosteviol 63 and commercially available glucosamine hydrochloride creating macrocycles, diterpenoid isosteviol 63 and commercially available glucosamine 65 were used and the entire synthesis can be divided into four stages (Scheme 10). In the hydrochloride 65 were used and the entire synthesis can be divided into four stages (Scheme 10). In ﬁrst stage, two isosteviol molecules were combined using a linker, and the carboxyl groups of the first stage, two isosteviol molecules were combined using a linker, and the carboxyl groups of isosteviol fragments were functionalized with hydroxypolymethylene chains, giving precursors 64a–b. isosteviol fragments were functionalized with hydroxypolymethylene chains, giving precursors 64a- Reactive carbohydrate 66 was obtained in a series of sequential reactions from glucosamine 65 by b. Reactive carbohydrate 66 was obtained in a series of sequential reactions from glucosamine 65 by introducing three acetate fragments, one trichloroethyl chloroformate protection of the amino group, introducing three acetate fragments, one trichloroethyl chloroformate protection of the amino group, and replacing the glycoside hydroxyl with bromine. Products 64a–b and 66 were then combined and replacing the glycoside hydroxyl with bromine. Products 64a-b and 66 were then combined to to form diglycosides 67a–b. Trichloroethylchloroformate protecting groups were removed from the form diglycosides 67a-b. Trichloroethylchloroformate protecting groups were removed from the amines before the target macrocyclic glycoterpenoids 68a–c were obtained by macrocyclization of amines before the target macrocyclic glycoterpenoids 68a-c were obtained by macrocyclization of 67a–b with alkydiisocyanates [45]. 67a-b with alkydiisocyanates [45].

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SchemeScheme 10.10. Synthesis ofof macrocyclicmacrocyclic glycoterpenoidsglycoterpenoids 68a68a−c. − Macrocycles 68a–c68a-c were tested for their ability to inhibit the growth of M. tuberculosis H37Rv cells in vitrovitro andand allall showedshowed moderatemoderate tuberculostatictuberculostatic activity.activity. TheirTheir minimumminimum inhibitoryinhibitory concentrations (MIC)(MIC) werewere inin the range 6.4–17.4 mM, while the MIC for the the antitubercular antitubercular drug isoniazid (the control compound in the experiment)experiment) waswas 0.70.7 mMmM [[45].45]. Spanish scientists synthesized [46] [46] polymetallic macrocyclic hybrids 73, 74, and 77 based on terpenoids. The two terpenoid fragments were linked together by a diyne linker, resultingresulting in thethe formation ofof structures structures that involvedthat involved a double a Nicholasdouble reactionNicholas to producereaction macrocyclic to produce meroterpenoids macrocyclic 73meroterpenoidsand 74. The 73 role and of the74. initialThe diynerole of linker the wasinitial performed diyne linker by 1,2-(bipropynyloxy)benzene was performed by 1,2- 69(bipropynyloxy)benzeneand 2,2-di(propynyl)malonate 69 and 2,2-di(propynyl)malonate70. Condensation of lithium 70. Condensation salts of compounds of lithium69 saltsand 70of withcompounds (1R)-(–)-myrtenal 69 and 70 with gave (1R)-(–)-myrtenal diols 71 and 72 gavein the diols form 71 and of diastereomeric72 in the form mixturesof diastereomeric in high yieldsmixtures (Scheme in high yields11). The (Scheme macrocycle 11). The wasmacrocyc formedle was through formed athrough double a double Nicholas Nicholas reaction reaction with 1,3,5-trimethoxybenzene.with 1,3,5-trimethoxybenzene. Macrocyclization Macrocyclization of one equivalentof one equivalent of compound of compound71 or 72 with 71 or one 72 equivalent with one ofequivalent 1,3,5-trimethoxybenzene of 1,3,5-trimethoxybenzene was carried outwas in carried the presence out in of the BF presenceOEt . Macrocyclic of BF3∙OEt compounds2. Macrocyclic73 3· 2 andcompounds74 were 73 obtained and 74 aswere individual obtained diastereoisomers as individual di (Schemeastereoisomers 11)[46 ].(Scheme 11) [46].

Plants 2020, 9, 1582 15 of 26 Plants 2020, 9, x FOR PEER REVIEW 15 of 27

SchemeScheme 11. 11.Reagents Reagents and and conditions: conditions: i,i, HMDSliHMDSli oror BuLi;BuLi; ii,ii, HH2O,O, NHNH4Cl; iii, Co2(CO)(CO)8;; iv, iv, BF BF3∙OEtOEt2. . 2 4 2 8 3· 2 Macrocycle 77 was also obtained from precursor 75 in twotwo stages.stages. CompoundCompound 75 was stereoselectively converted converted to to the the Co Co2(CO)2(CO)6-bis-alkyne6-bis-alkyne complex complex 76 76followedfollowed by cyclization by cyclization with with 1,4- 1,4-benzenedimethanolbenzenedimethanol in the in presence the presence of BF of3∙OEt BF32OEt to obtain2 to obtain macrocycle macrocycle 77 in 77almostin almost quantitative quantitative yield benzenedimethanol in the presence of BF3∙OEt·2 to obtain macrocycle 77 in almost quantitative yield yield(Scheme (Scheme 12). 12).

Scheme 12.12. Reagents and conditions:conditions: i, Co2(CO)(CO)88, ,DCM, DCM, rt; rt; ii, 1,4-Benzenedimethanol,1,4-Benzenedimethanol, dioxane, BF3∙OEt2;; iii, iii, BF BF3∙OEtOEt2. . 3· 2 3· 2

Ju et al. [[47]47] synthesized macrocycle 82 from 18b-glycyrrhetinic acid, acid, 7878,, using using click click chemistry. chemistry. Glycyrrhetinic acid, 78 (Scheme 1313),), reacted with proparogyl bromide in the presence of cesiumcesium carbonate to give 79 in a yield of 89%. Subsequent Subsequent acylation acylation gave gave bromo bromo derivative derivative 8080 inin good good yield. yield. For the ﬁnalfinal stage of cyclization, precursor 80 was converted to azide 81 in preparation for a Huisgen reaction toto form the target macrocycle 8282 inin 11%11% yieldyield (Scheme(Scheme 1313).). Macrocycle 82 showed selectivity 2+ in recognizingrecognizing ﬂuoridefluoride andand HgHg2+ ionsions through through binding to the 1,2,3-triazole moiety andand carbonylcarbonyl group, respectively.

Plants 2020, 9, 1582 16 of 26 Plants 2020, 9, x FOR PEER REVIEW 16 of 27

Scheme 13.13. Reagents andand conditions:conditions: i,i, PropargylPropargyl bromide,bromide, CsCs22COCO33, DMF;DMF; ii,ii, BrCHBrCH22C(O)Br, KK22CO3,, CHCl3;; iii iii NaN NaN3,, DMF; DMF; iv, iv, CuSO CuSO4∙5H5H2O,O, Sodium Sodium ascorbate, ascorbate, t-BuOH–H t-BuOH–H2O–THFO–THF (5:1:2). (5:1:2). 3 3 4· 2 2

Metacyclophanes and paracyclophanes are among the most well-studied class of macrocyclic compounds andand include include the the calix[n]arenes, calix[n]arenes, important import macrocyclicant macrocyclic platforms platforms exhibiting exhibiting various receptorvarious propertiesreceptor properties depending depending on their size on and their conformation size and conformation [48–53], (thia)calix[n]arenes, [48–53], (thia)calix[n]arenes, and pillar[n]arenes. and pillar[n]arenes.To date, various macrocyclic systems and supramolecular assemblies based on (thia)calixarenes haveTo been date, developed various macrocyclic and synthesized systems [54 –and56]. supramol A groupecular of Chinese assemblies scientists based led on by (thia)calixarenes Lai synthesized calix[4]areneshave been developed85a–b and and 86asynthesized–b, containing [54–56]. triterpenoid A group of (cholesterol) Chinese scientists fragments led by which Lai synthesized had liquid crystalcalix[4]arenes properties 85a- [b53 and]. Cholesterol, 86a-b, containing73, is often triterpenoid used as (cholesterol) a good structural fragments unit forwhich the creationhad liquid of variouscrystal properties types of liquid [53]. crystalCholesterol, materials 73, is with often interesting used as mesomorphica good structural properties unit for [57 the–61 creation]. The first of liquidvarious crystals types of were liquid obtained crystal frommaterials calix[4]arene-cholesterol with interesting mesomorphic derivatives properties85a–b and [57–61].86a–b (SchemeThe first XIV),liquidwhich crystals were were synthesized obtained infrom 50–80% calix[4]arene-cholesterol yields [57]. The synthetic derivatives pathway, 85a- Schemeb and 86a 14,-b shows (Scheme the alkylationXIV), which of werep-tert -butylthiacalix[4]arenesynthesized in 50–80% with yields cholesterol [57]. The derivatives synthetic pathway,74a–b and Scheme allowed 14, the shows synthesis the ofalkylation di- and tetrasubstitutedof p-tert-butylthiacalix[4]arene macrocycles 85a– bwithand 86acholesterol–b. The yield derivatives of disubstituted 74a-b and products allowed is higher the thansynthesis that of di- the and tetrasubstituted, tetrasubstituted which macrocycles is most likely85a-b dueand 86a to steric-b. The hindrance yield of disubstituted in the reaction products with a cholesterolis higher than derivative. that of the Di tetrasubstituted,fferential scanning which calorimetry is most likely (DSC) due was to used steric in hindrance the preliminary in the studyreaction of thewith mesomorphic a cholesterol behaviorderivative. of compoundsDifferential scanni85a–bngand calorimetry86a–b. All (DSC) new compounds was used in have the twopreliminary thermal peaksstudy onof the the mesomorphic second heating behavior and cooling, of compounds respectively. 85a Judging-b and 86a by- theb. All heats new of compounds fusion and hysteresishave two betweenthermal peaks the peaks on the of second crystallization heating andand melting,cooling, respectively. for compounds Judging85a– bbyand the86a heats–b thereof fusion are twoand solid-state-mesophasehysteresis between the peaks and mesophase-isotropic of crystallization and phase melting, transitions for compounds upon cooling 85a-b andand heating,86a-b there which are istwo also solid-state-mesophase confirmed by the data and of mesophase-isotropic polarization optical microscopyphase transitions (POM). upon Compounds cooling and85b andheating,86b representwhich is also a broader confirmed mesophase by the data spectrum of polarization than compounds optical microscopy85a and 86a (POM)., suggesting Compounds that the 85b spacers and between86b represent the cholesterol a broader moiety mesophase and calixarene spectrum strongly than compounds affect the mesomorphic 85a and 86a, properties.suggesting Thethat long the spacerspacers proved between to the be morecholesterol suitable moiety so that and each calixar partene of thestrongly structure affect could the mesomorphic find its own counterpart properties. inThe the long resulting spacer mesophase. proved to be Moreover, more suitable the mesomorphic so that each temperature part of the rangestructure of compounds could find 86aits ownand 86bcounterpartwith four in cholesterol the resulting units wasmesophase. greater than More thatover, of compounds the mesomorphic85a and 85btemperaturewith two cholesterolrange of units.compounds These 86a results and 86b showed with four that cholesterol the number units of cholesterol was greater units than also that playsof compounds an important 85a and role 85b in mesomorphicwith two cholesterol properties. units. The These more results cholesterol showed units th wereat the in number the compound, of cholesterol the wider units the also mesophase plays an temperatureimportant role range. in mesomorphic For compounds properties.85a–b andThe 86amore–b ,cholesterol clear textures units were were observed in the compound, upon cooling. the Thesewider texturesthe mesophase were similar temperature to typical range. focal-conical For compounds columnar 85a liquid-b and crystals, 86a-b, whichclear textures were further were confirmedobserved upon by X-ray cooling. diff ractionThese textures analysis. were In addition, similar to X-ray typical diff focal-conicalraction showed columnar that di liquidfferent crystals, lengths which were further confirmed by X-ray diffraction analysis. In addition, X-ray diffraction showed

Plants 2020, 9, x FOR PEER REVIEW 17 of 27 that different lengths of spacers and different amounts of cholesterol units in the calixarene structure affected the crystal packing to a certain extent [57]. Cholesterol moieties in the calixarene structure are also used to obtain the properties of gels. PlantsThus, 2020 a group, 9, x FOR of PEER Indian REVIEW scientists led by Rao reported [62] the synthesis of monosubstituted 17p-tert of 27- butylthiacalix[4]arene, 88, functionalized with a triterpenoid cholesterol fragment. The target thatcompound different was lengths synthesized of spacers by an done-stage different condamountsensation of cholesterol of chloroformylcholesterol units in the calixarene with structure p-tert- affectedbutylcalix[4]arene the crystal (Scheme packing 15).to a Productcertain extent 88 was [57]. characterized by 1H and 13C NMR, ESI-MS, FTIR, and elementalCholesterol analysis moieties [62]. in the calixarene structure are also used to obtain the properties of gels. PlantsThus,2020 a group, 9, 1582 of Indian scientists led by Rao reported [62] the synthesis of monosubstituted 17p-tert of 26- butylthiacalix[4]arene, 88, functionalized with a triterpenoid cholesterol fragment. The target compound was synthesized by one-stage condensation of chloroformylcholesterol with p-tert- ofbutylcalix[4]arene spacers and diﬀ (Schemeerent amounts 15). Product of cholesterol 88 was characterized units in the calixarene by 1H and structure13C NMR, a ESI-MS,ﬀected the FTIR, crystal and packingelemental to analysis a certain [62]. extent [57].

Scheme 14. Reagents and conditions: i, Cl(CH2)nCOOH, DCC, DMAP, CH2Cl2; ii, 84a (or 84b), K2CO3,

KI, MeCN; iii, 84a (or 84b), K2CO3, KI, MeCN.

The gel capability of 88 was tested in twenty organic solvents and demonstrated versatile gelling properties with various solvent combinations. The minimum concentration of 88 in the gel agent in

THF/acetonitrileScheme 14. Reagents (1:1) was and conditions:0.6 wt%. i,SEM Cl(CH and22)nCOOH, AFM DCC, images DMAP, of the CHCH 22ClgelCl22; ii,showed 84a (or 84ba ),well-ordered), KK22CO3,, nanostructuredKI, MeCN; iii, system, 84a (or 84b while),), KK22CO the3,, KI, KI,sol MeCN. MeCN. showed spherical nanoaggregates. The ability of the synthesized compounds to interact with rhodamine, fluorescein, doxorubicin, curcumin, and tocopherylCholesterolThe gel acetate capability moieties was ofshown 88 in was theby tested fluorescence calixarene in twenty structurespectroscopy, organicare solven alsowhilets and used gel demonstrated processes to obtain were the versatile also properties observed. gelling of gels.propertiesDetailed Thus, fluorescence with a group various of measurements Indian solvent scientists combin clearlyations. led by confir The Rao minimummed reported the uptake [concentration62] the of synthesis drug ofcompounds 88 of in monosubstituted the gel in agentthe gel. in p-tertTHF/acetonitrileQuantum-chemical-butylthiacalix[4]arene, (1:1) modeling was 0.688 showed ,wt%. functionalized SEMthat thandere with isAFM an a interaction triterpenoidimages of between the cholesterol gel theshowed guest fragment. πa -systemswell-ordered The target with compoundnanostructuredthe C-H cholesteric was synthesizedsystem, fragment, while by indicating one-stage the sol condensation thatshowed the captured spherical of chloroformylcholesterol guest nanoaggregates. molecules are stabilized withThe p-tertability due-butylcalix toof C-Hthe 1 13 [4]arenesynthesized∙∙∙ π-interactions. (Scheme compounds 15 Encapsulated). Product to 88interact wasguests characterized with are rhodameasily by releasedine,H andfluorescein, whenC NMR, the doxorubicin, ESI-MS,gel is heated FTIR, curcumin, and above elemental room and analysistocopheryltemperature [62 acetate]. [62]. was shown by fluorescence spectroscopy, while gel processes were also observed. Detailed fluorescence measurements clearly confirmed the uptake of drug compounds in the gel. Quantum-chemical modeling showed that there is an interaction between the guest π-systems with the C-H cholesteric fragment, indicating that the captured guest molecules are stabilized due to C-H ∙∙∙ π-interactions. Encapsulated guests are easily released when the gel is heated above room temperature [62].

Scheme 15. ReagentsReagents and and conditions: conditions: i, i,Cholesteryl Cholesteryl chloroformate, chloroformate, K K2CO2CO3, NaI,3, NaI, dry dry acetone, acetone, reflux reﬂux for for 15 15h. h.

The gel capability of 88 was tested in twenty organic solvents and demonstrated versatile gelling properties with various solvent combinations. The minimum concentration of 88 in the gel agent in THF/acetonitrile (1:1) was 0.6 wt%. SEM and AFM images of the gel showed a well-ordered Scheme 15. Reagents and conditions: i, Cholesteryl chloroformate, K2CO3, NaI, dry acetone, reflux for 15 nanostructuredh. system, while the sol showed spherical nanoaggregates. The ability of the synthesized compounds to interact with rhodamine, fluorescein, doxorubicin, curcumin, and tocopheryl acetate was shown by fluorescence spectroscopy, while gel processes were also observed. Detailed fluorescence measurements clearly confirmed the uptake of drug compounds in the gel. Quantum-chemical modeling showed that there is an interaction between the guest π-systems with the C-H cholesteric Plants 2020, 9, 1582 18 of 26 fragment, indicating that the captured guest molecules are stabilized due to C-H π-interactions. ··· Encapsulated guests are easily released when the gel is heated above room temperature [62]. A group led by Zhao synthesized [63] calix[4]arene 95, functionalized on the upper rim with triterpenoidPlants 2020, 9, x (cholesterol)FOR PEER REVIEW fragments (Figure 10 and Scheme 16). 19 of 27

Plants 2020, 9, x FOR PEER REVIEW 18 of 27

A group led by Zhao synthesized [63] calix[4]arene 95, functionalized on the upper rim with triterpenoidFigure 10. (cholesterol) Structures offragments amphiphilic (Figure calix[4]arenes 10 and Scheme containing 16). cholesterol fragmentsfragments 96a–b96a-b, 97, 98.

Carreira’s group [64] synthesized new calix[4]arene derivatives 99 and 100 (Figure 11), containing four meroterpenoid fragments (amphotericin B). The synthesized macromolecules assume a cone-shaped conformation that mimics the structure of a transmembrane pore. The antifungal activity of derivatives 90 and 100 was similar to amphotericin B with the minimum inhibitory concentrations of 0.10 and 0.25 μM, respectively. In addition, the hemotoxicity of the new derivatives was significantly lower (at least 10×) than the hemotoxicity of monomeric amphotericin B. Finally, the ability of compounds 99 and 100 was shown to form ion channels in the lipid bilayer [64].

SchemeScheme 16. 16.Reagents Reagents andand conditions:conditions: i, TsCl, Pyridine; ii, NaN3,, DMPU; DMPU; iii, iii, PPh PPh33, ,THF/H THF/H2O;2O; iv, iv, Cholic Cholic acid,acid, BOP, BOP, DIPEA; DIPEA; v, v, LiOH; LiOH; vi, vi, HO-Su, HO-Su, DCC, DCC, vii, vii,94 94..

TheThe compounds compounds obtainedobtained areare amphiphilicamphiphilic macrocycles with with one one ( (96a96a-–bb, ,9797 andand 9898) )(Figure (Figure 10) 10 ) oror two two ( 95(95)) (Scheme (Scheme 16 16)) cholesterolcholesterolFigure fragmentsfragments11. Structures on of the macrocycles u upperpper rim rim 99 of of-100 the the. tetrasubstituted tetrasubstituted macrocycle. macrocycle. TheThe conformational conformational rigidityrigidity ofof thethe spacerspacer betweenbetween the terpenoid and and macrocyclic macrocyclic parts parts also also varies varies withwithA rigid rigid group 4-aminobenzoyl 4-aminobenzoyl led by Yamada ((9797 [65])) oror syntﬂexibleflexiblehesized 4-aminobutyroyl4-aminobutyroyl steroid metacyclophans (98) linkers. 103The The andsynthesized synthesized 104 (Scheme macrocycles macrocycles 17). The withauthorswith cholesterol cholesterol carried fragmentsout fragments regioselective attached attached macrocyclization to theto the macrocyclic macrocyclic of framework methylcholate framework can formcan101 formusing multiple multiple dimethyl- hydrogen hydrogenα,α bonds,α',α'- duetetramethyl-bonds to thedue presence tom-xylylenedicarbamate the presence of secondary of secondary amide 102. The amide groups. reaction groups. Due was toDue carried this, to calix[4]arenesthis, out bycalix[4]arenes transesterification95-98 95can-98 easilycan in boilingeasily form tolueneform supramolecular (0.004 M) using assemblies3% SnCl2 and with 1% theglycoluril formation as catalysts. of monomolecular After 2 h of reaction,and reversed product micelles. 103 has beenContainers obtained based selectively on calix[4]arenes in high yield 95-98 (9 give4%). stable Conversion micelles of regardless 16-membered of the macrocycle nature of the 103 rigidity to 18- memberedof the spacer. cyclophane The authors 104 suggestwas achieved that choleste by equilibrationrol fragments in directly7 days toattached obtain tothermodynamically macrocycle 95 in stablepolar 104solvents in yield have 68%. fewer New degrees steroidal of carbamoyloxy-bridgingfreedom in comparison cyclophanswith terminal 103 cholesterol and 104 are fragments, examples ofwhich regioisomeric leads to the steroi formationdal cyclophans of more ordered [65]. supramolecular structures of calix[4]arene 95 compared to 96-98 (Figure 10) [63].

Plants 2020, 9, x FOR PEER REVIEW 19 of 27

Plants 2020, 9, 1582 19 of 26 supramolecular assemblies with the formation of monomolecular and reversed micelles. Containers based on calix[4]arenes 95-98 give stable micelles regardless of the nature of the rigidity of the spacer. The authors suggest that cholesterol fragments directly attached to macrocycle 95 in polar solvents have fewer degrees of freedom in comparison with terminal cholesterol fragments, which leads to theFigure formation 10. Structures of more of ordered amphiphilic supramolecular calix[4]arenes structures containing ofcholesterol calix[4]arene fragments95 compared 96a-b, 97, 98 to. 96-98 (Figure 10)[63]. Carreira’s group group [64] [64 synthesize] synthesizedd new newcalix[4]arene calix[4]arene derivatives derivatives 99 and 10099 and(Figure100 11),(Figure containing 11), containingfour meroterpenoid four meroterpenoid fragments (amp fragmentshotericin (amphotericin B). The synthesized B). The synthesizedmacromolecules macromolecules assume a cone-shaped assume a cone-shapedconformation conformation that mimics the that structure mimics of the a structuretransmembrane of a transmembrane pore. The antifungal pore. The activity antifungal of derivatives activity of90 derivativesand 100 was90 similarand 100 to wasamphotericin similar to B amphotericin with the minimu B withm inhibitory the minimum concentrations inhibitory of concentrations 0.10 and 0.25 ofμM, 0.10 respectively. and 0.25 µM, In respectively.addition, the Inhemotoxicity addition, the of hemotoxicity the new derivatives of the new was derivatives significantly was lower signiﬁcantly (at least lower10×) than (at the least hemotoxicity 10 ) than of the monomeric hemotoxicity amphot of monomericericin B. Finally, amphotericin the ability of B. compounds Finally, the 99 ability and 100 of × compoundswas shown to99 formand ion100 channelswas shown in the to lipid form bilayer ion channels [64]. in the lipid bilayer [64].

FigureFigure 11.11. Structures ofof macrocyclesmacrocycles 9999–-100.

A group led led by by Yamada Yamada [65] [65 synt] synthesizedhesized steroid steroid metacyclophans metacyclophans 103103 andand 104 104(Scheme(Scheme 17). The17). Theauthors authors carried carried out outregioselective regioselective macrocyclization macrocyclization of methylcholate of methylcholate 101101 usingusing dimethyl- dimethyl-α,αα,,αα',,α'-’, αtetramethyl-’-tetramethyl-m-xylylenedicarbamatem-xylylenedicarbamate 102.102 The. reaction The reaction was carried was carried out by out transesterification by transesteriﬁcation in boiling in boilingtoluenetoluene (0.004 M) (0.004 using M) 3% using SnCl 3%2 and SnCl 1%2 andglycoluril 1% glycoluril as catalysts. as catalysts. After 2 h After of reaction, 2 h of reaction, productproduct 103 has 103beenhas obtained been obtained selectively selectively in high in yield high (9 yield4%). (94%). Conversion Conversion of 16-membered of 16-membered macrocycle macrocycle 103 103to 18-to 18-memberedmembered cyclophane cyclophane 104104 waswas achieved achieved by by equilibration equilibration in in 7 7 days days to to obtain thermodynamicallythermodynamically stable 104 inin yieldyield 68%.68%. New steroidal carbamoyloxy-bridging cyclophans 103 and 104 are examples of regioisomeric steroidalsteroidal cyclophanscyclophans [[65].65].

Plants 2020, 9, 1582 20 of 26 Plants 2020,, 9,, xx FORFOR PEERPEER REVIEWREVIEW 20 of 27

SchemeScheme 17.17. Reagents and conditions: i, 3% SnCl 22,,, 1%1% 1% glycouril,glycouril, glycouril, toluene,toluene, toluene, reflux.reflux. reﬂux.

As a lowlow molecularmolecular weightweight gellinggelling agent,agent, LeyongLeyong WangWang etet al.al. synthesizedsynthesized a pillar[6]arenepillar[6]arene functionalizedfunctionalized withwith aa de derivativederivative of of cholesterol 105 (Figure(Figure 12),1212),), whichwhich forms forms an an organogel organogel in in a a cyclohexane/n-hexanolcyclohexane/n-hexanol mixture mixture (10:1 (10:1 V/V) V/V) at 10 °C◦C... The The resulting resulting organogel organogel reacts reacts reversibly reversibly to to temperaturetemperature changeschanges andand formsforms guest–hostguest–host complexescomplexes [[66].[66].66].

Figure 12. StructureStructure of pillar[6]arene 105..

Varshosaz et al. [67] successfully synthesized meroterpenoid 106 (Figure 13) based on Varshosaz et al. [67] successfully synthesized meroterpenoid 106 (Figure(Figure 13)13) basedbased onon β-- β-cyclodextrin, folic, and retinoic acid which formed stable submicron self-associates in water. cyclodextrin, folic, and retinoic acid which formed stablestable submicronsubmicron self-associatesself-associates inin water.water. TheThe The stability of the formed colloidal system was additionally confirmed by measuring the value of stability of the formed colloidal system was additionally confirmed by measuring the value of the ζ-- the ζ-potential. It was shown that macrocycle 106 (Figure 13) is able to effectively encapsulate the potential. It was shown that macrocycle 106 (Figure(Figure 13)13) isis ableable toto effectivelyeffectively encapsulateencapsulate thethe anticancer drug, doxorubicin [67]. anticancer drug, doxorubicin [67]. In 2016 a series of water-soluble meroterpenoids 107–109 (Figure 14) was synthesized based on α-cyclodextrin/pentacyclic hopanoids (110–113) (Figure 14) and obtained in good yields [68]. Inhibiting the entry of HCV (hepatitis C virus) is a key goal in the treatment of chronic hepatitis C virus infection. HCV entry inhibition activity was determined based on HCVpp/VSVGpp penetration assays. The best results were found for compounds 107 and 108, which showed the most promising activity inhibition of HCV penetration with mean IC50 values of 1.18 mM and 0.25 mM. In addition, the in vitro cytotoxic activity of these two compounds against MDCK cells was absent even at 100 mM. Five different binding assays were identified to determine the mechanism of action; the results showed that the compounds exhibit their inhibitory activity at the stage after HCV binding and subsequently prevent the penetration of the virus [68].

Plants 2020, 9, 1582 21 of 26 Plants 2020, 9, x FOR PEER REVIEW 21 of 27

Plants 2020, 9, x FOR PEER REVIEW Figure 13.13. Structure of macrocycle 106106.. 22 of 27

In 2016 a series of water-soluble meroterpenoids 107-109 (Figure 14) was synthesized based on α-cyclodextrin/pentacyclic hopanoids (110-113) (Figure 14) and obtained in good yields [68]. Inhibiting the entry of HCV (hepatitis C virus) is a key goal in the treatment of chronic hepatitis C virus infection. HCV entry inhibition activity was determined based on HCVpp/VSVGpp penetration assays. The best results were found for compounds 107 and 108, which showed the most promising activity inhibition of HCV penetration with mean IC50 values of 1.18 mM and 0.25 mM. In addition, the in vitro cytotoxic activity of these two compounds against MDCK cells was absent even at 100 mM. Five different binding assays were identified to determine the mechanism of action; the results showed that the compounds exhibit their inhibitory activity at the stage after HCV binding and subsequently prevent the penetration of the virus [68].

Figure 14. Structures of compounds 107–113107-113..

The resultsresults obtainedobtained are are in in good good agreement agreement with with studies studies carried carried out out on β on-cyclodextrins β-cyclodextrins [69]. [69]. It was It previouslywas previously found thatfound oleanolic that oleanolic acid 110 andacid echinocystic 110 and acidechinocystic111, isolated acid from 111Dipsacusasperoides, isolated from, Dipsacusasperoides, have the properties of inhibiting HCV penetration. The main problem in using this type of triterpenes is their low aqueous solubility. Thus, the introduction of fragments of hopanoids

(110-113) into the structure of α- and β-cyclodextrins increases the solubility of terpenes in water. In the case of β-cyclodextrin 114 meroterpenoid (Figure 15), moderate activity inhibition of HCV penetration was found. All synthesized meroterpenoids showed no cytotoxicity based on the alamarBlue assay performed on HeLa, HepG2, MDCK, and 293T cells. It should also be noted that when the terpene and β-cyclodextrin structures were combined, the obtained triterpenes became hemolytically inactive. A simple synthetic approach to the preparation of meroterpenoids, combining the properties of β-cyclodextrin and pentacyclic triterpenoids, based on the concept of “click chemistry”, can provide a way to obtain a new class of inhibitors of HCV penetration [68,69].

Plants 2020, 9, 1582 22 of 26 have the properties of inhibiting HCV penetration. The main problem in using this type of triterpenes is their low aqueous solubility. Thus, the introduction of fragments of hopanoids (110–113) into the structure of α- and β-cyclodextrins increases the solubility of terpenes in water. In the case of β-cyclodextrin 114 meroterpenoid (Figure 15), moderate activity inhibition of HCV penetration was found. All synthesized meroterpenoids showed no cytotoxicity based on the alamarBlue assay performed on HeLa, HepG2, MDCK, and 293T cells. It should also be noted that when the terpene and β-cyclodextrin structures were combined, the obtained triterpenes became hemolytically inactive. A simple synthetic approach to the preparation of meroterpenoids, combining the properties of β-cyclodextrin and pentacyclic triterpenoids, based on the concept of “click chemistry”, can provide a wayPlants to2020 obtain, 9, x FOR a new PEER class REVIEW of inhibitors of HCV penetration [68,69]. 23 of 27

Figure 15. Structure of macrocycle 114.

Thus, the variety of synthetic, macrocyclic meroterpenoids leads to the conclusion that the Thus, the variety of synthetic, macrocyclic meroterpenoids leads to the conclusion that the development of new generation materials with biologically significant properties is impossible without development of new generation materials with biologically significant properties is impossible the use of natural products. Terpenoids, such as natural products, are ideal for these purposes, without the use of natural products. Terpenoids, such as natural products, are ideal for these as they have low toxicity and are completely biocompatible. The advantages of targeted synthesis of purposes, as they have low toxicity and are completely biocompatible. The advantages of targeted macrocyclic meroterpenoids include: (1) ease of production (a variety of synthetic methods makes synthesis of macrocyclic meroterpenoids include: (1) ease of production (a variety of synthetic it easy to vary the structure of the target meroterpenoids), (2) scalability (the developed synthetic methods makes it easy to vary the structure of the target meroterpenoids), (2) scalability (the methods allow obtaining a large amount of substance in a short time), (3) independence from external developed synthetic methods allow obtaining a large amount of substance in a short time), (3) conditions (any specialist equipped with the appropriate equipment, can easily reproduce the synthetic independence from external conditions (any specialist equipped with the appropriate equipment, can method). However, the directed synthesis of macrocyclic meroterpenoids has one very important easily reproduce the synthetic method). However, the directed synthesis of macrocyclic drawback, which is the loss of biological activity of the terpenoid fragment, which is part of the meroterpenoids has one very important drawback, which is the loss of biological activity of the macrocyclic compound, caused by chemical modification. This disadvantage must always be taken terpenoid fragment, which is part of the macrocyclic compound, caused by chemical modification. into account when drawing up a synthetic strategy. This disadvantage must always be taken into account when drawing up a synthetic strategy. 4. Conclusions 4. Conclusions It can be concluded that the development of the chemistry of macrocyclic meroterpenoids will It can be concluded that the development of the chemistry of macrocyclic meroterpenoids will make it possible to design new highly effective drugs and create a new generation of nontoxic materials. make it possible to design new highly effective drugs and create a new generation of nontoxic Large reserves of renewable natural raw materials will be able to contribute to research aimed at materials. Large reserves of renewable natural raw materials will be able to contribute to research obtaining and establishing patterns of “structure-activity” of new classes of macrocyclic meroterpenoids. aimed at obtaining and establishing patterns of “structure-activity” of new classes of macrocyclic Analysis of the literature has shown that in recent years there has been a steady tendency to abandon meroterpenoids. Analysis of the literature has shown that in recent years there has been a steady the use of natural raw materials as sources of macrocyclic meroterpenoids. The main work in this area tendency to abandon the use of natural raw materials as sources of macrocyclic meroterpenoids. The is carried out by combining synthetic and natural compounds into one hybrid macrocyclic platform. main work in this area is carried out by combining synthetic and natural compounds into one hybrid macrocyclic platform. Among these synthetic macrocyclic platforms, (thia)calix[n]arenes, pillar[n]arenes, and cyclodextrins, occupy a special place. The introduction of terpene fragments into their structure leads to a decrease in toxicity, an increase in the affinity for the cell membrane, as well as the processes of self-association and aggregation of macrocyclic meroterpenoids. Such unique compounds will find use both in targeted drug delivery systems and as drugs themselves. Another approach to the creation of macrocyclic meroterpenoids is the assembly of macrocyclic frameworks by macrocyclization of individual terpene fragments. This approach allows one to obtain such unique macrocycles as cholaphanes and cyclocholates. Advances in the chemistry and biology of meroterpenoids and their macrocyclic derivatives opened the way of use the potential of these biological objects to discover and predict the properties of next-generation natural products through the development of biochemical pathways such as combinatorial biosynthesis. A detailed understanding of the complex enzymatic mechanisms

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Among these synthetic macrocyclic platforms, (thia)calix[n]arenes, pillar[n]arenes, and cyclodextrins, occupy a special place. The introduction of terpene fragments into their structure leads to a decrease in toxicity, an increase in the affinity for the cell membrane, as well as the processes of self-association and aggregation of macrocyclic meroterpenoids. Such unique compounds will find use both in targeted drug delivery systems and as drugs themselves. Another approach to the creation of macrocyclic meroterpenoids is the assembly of macrocyclic frameworks by macrocyclization of individual terpene fragments. This approach allows one to obtain such unique macrocycles as cholaphanes and cyclocholates. Advances in the chemistry and biology of meroterpenoids and their macrocyclic derivatives opened the way of use the potential of these biological objects to discover and predict the properties of next-generation natural products through the development of biochemical pathways such as combinatorial biosynthesis. A detailed understanding of the complex enzymatic mechanisms involved in the production of macrocyclic secondary metabolites is still awaiting detailed explanation. Progress in this direction will provide expansion of the range of detectable macrocyclic derivatives and predict their potential applications. In addition, it will create the basis for rational efforts in enzyme bioengineering for further expansion of the chemical diversity of meroterpenoids and allow the discovery of valuable new compounds. The transfer of the accumulated knowledge to the field of synthetic methods of production will make it possible to obtain target macrocyclic compounds in large quantities, while preserving the Earth’s valuable biological resources.

Author Contributions: Conceptualization, I.I.S.; writing—original draft preparation, A.A.A., D.N.S.; writing—review and editing, P.J.C., V.V.P. All authors have read and agreed to the published version of the manuscript. Funding: The study was funded by RFBR according to research project № 18-03-00315, № 19-33-90170 and the grant of the President of the Russian Federation for state support of leading scientific schools of the Russian Federation (NSh-2499.2020.3). Conflicts of Interest: The authors declare no conflict of interest.

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