Anticancer Agentsagents

pharmaceuticals

ReviewReview MonofunctionalMonofunctional Platinum(II)Platinum(II) AnticancerAnticancer AgentsAgents

1,† 1,2,† 1 3, SuxingSuxing JinJin 1,†, Yan, Yan Guo Guo 1,2,†, Zijian, Zijian Guo Guo and1 and Xiaoyong Xiaoyong Wang Wang * 3,*

1 StateState K Keyey Laboratory Laboratory of of Coordination Coordination Chemistry, Chemistry, School School of Chemistry and Chemical Engineering, Nanjing University,Nanjing University, Nanjing 210023 Nanjing, China 210023,; [email protected] China; [email protected] (S.J.); [email protected] (S.J.); [email protected] (Y.G.); (Y.G.); [email protected]@nju.edu.cn (Z.G (Z.G.).) 22 SchoolSchool of of Materials Materials and and Chemical Chemical Engineerin Engineering,g, Henan Henan University University of of Urban Urban Construction, Construction, Pingdingshan 467036,Pingdingshan China 467036, China 33 StateState Key Key Laboratory Laboratory of of Pharmaceutical Pharmaceutical Biotechnology, Biotechnology, School School of Life Sciences, Nanjing University, Nanjing 2100Nanjing23, China 210023, China ** Correspondence:Correspondence: [email protected] [email protected] †† These These authors authors contributed contributed equally equally to to this this article. article.

Abstract:Abstract: Platinum-basedPlatinum-based anticancer drugs represented by cisplatin cisplatin play play important important roles roles in in the the treatmenttreatment ofof variousvarious solidsolid tumors.tumors. However,However, theirtheir applicationsapplications areare largelylargely compromisedcompromised byby drugdrug resistanceresistance andand sideside effects.effects. MuchMuch efforteffort hashas beenbeen made to circumvent thethe drugdrug resistance andand generalgeneral toxicitytoxicity ofof thesethese drugs.drugs. AmongAmong multifariousmultifarious designs,designs, monofunctionalmonofunctional platinum(II)platinum(II) complexescomplexes withwith aa generalgeneral formulaformula ofof [Pt(3A)Cl][Pt(3A)Cl]++ (A(A:: A Ammoniammonia or amine) stand out as a class of “non-traditional”“non-traditional” anticanceranticancer agentsagents hopefulhopeful toto overcomeovercome thethe defectsdefects ofof currentcurrent platinumplatinum drugs.drugs. ThisThis reviewreview aimsaims toto summarizesummarize thethe developmentdevelopment ofof monofunctionalmonofunctional platinum(II)platinum(II) complexescomplexes inin recentrecent years.years. TheyThey areare classifiedclassified intointo fourfour categories:categories: fluorescentfluorescent complexes,complexes, photoactivephotoactive complexes,complexes, targetedtargeted complexes,complexes, andand miscellaneousmiscellaneous complexes.complexes. The intention behind the designsdesigns is eithereither toto visualizevisualize thethe cellularcellular distribution,distribution, or to reducereduce thethe sideside effects,effects, oror toto improveimprove thethe tumortumor selectivity,selectivity, oror inhibitinhibit thethe cancercancer cellscells throughthrough non-DNAnon-DNA targets. targets. The The information information provided provided by by this this review review may may inspire inspire researchers researchers to conceiveto conceive more more innovative innovative complexes complexes with with potent potent efficacy efficacy to to shake shake off off the the drawbacks drawbacks of of platinumplatinum anticanceranticancer drugs.drugs. Citation: Jin, S.; Guo, Y.; Guo, Z.; Citation: Jin, S.; Guo, Y.; Guo, Z.; Wang, X. Monofunctional - Wang, X. Monofunctional Keywords:Keywords: anticanceranticancer drug;drug; drugdrug design;design; metal-basedmetal based drug; drug; monofunctional monofunctional platinum platinum complex complex Platinum(II) Anticancer Agents. Platinum(II) Anticancer Agents. Pharmaceuticals 2021, 14, x. Pharmaceuticals 2021, 14, 133. https://doi.org/10.3390/xxxxx https://doi.org/10.3390/ph14020133 1.1. IntroductionIntroduction Academic Editor: Guido Crisponi Academic Editor: Guido Crisponi Received: 12 January 2021 CisplatinCisplatin andand itsits analogues,analogues, carboplatin,carboplatin, oxaliplatin,oxaliplatin, nedaplatin [[1],1], lobaplatin [[2],2], Received: 12 January 2021 Accepted: 4 February 2021 andand heptaplatinheptaplatin [3] [3] (Figure 11)) have been approved for for clinical clinical use use in in different different countries countries to Accepted: 4 February 2021 Published: 7 February 2021 totreat treat multiple multiple solid solid neoplasms, neoplasms, and and a approximatelypproximately half half of of the chemotherapychemotherapy strategiesstrategies Published: 7 February 2021 includeinclude platinumplatinum drugsdrugs [[44––66].]. However,However, thesethese drugsdrugs areare structuralstructural congenerscongeners ofof cisplatincisplatin Publisher’s Note: MDPI stays neu- andand therefore,therefore, somesome drawbacksdrawbacks areare inheritedinherited [[77––99].]. ForFor instance,instance, DNADNA isis believedbelieved toto bebe Publisher’s Note: MDPI stays neutral tral with regard to jurisdictional the ultimate target of cisplatin, so are other platinum drugs [10–12]. Nevertheless, DNA with regard to jurisdictional claims in the ultimate target of cisplatin, so are other platinum drugs [10–12]. Nevertheless, DNA claims in published maps and institu- damages could be easily repaired by DNA repair mechanisms. Therefore, all the existing published maps and institutional affil- damages could be easily repaired by DNA repair mechanisms. Therefore, all the existing tional affiliations. iations. platinumplatinum anticanceranticancer drugsdrugs encounterencounter drugdrug resistanceresistance [[1313,,1414].]. Moreover,Moreover, theirtheir nonspecificnonspecific accumulationaccumulation inin thethe hypermetabolichypermetabolic statestate tissuestissues resultsresults inin thethe systemicsystemic toxicity.toxicity.

Copyright: © 2021 by the authors. Li- Copyright:censee MDPI,© 2021 Basel, by Switzerland. the authors. LicenseeThis article MDPI, is an Basel,open access Switzerland. article Thisdistributed article under is an openthe terms access and article con- distributedditions of the under Creative the Commons terms andAt- conditionstribution (CC of theBY) Creativelicense (http://crea- Commons Attributiontivecommons.org/licenses/by/4.0/). (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). FigureFigure 1.1. Chemical structures ofof clinicallyclinically approvedapproved platinumplatinum anticanceranticancer drugs.drugs.

Pharmaceuticals 2021, 14, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 133. https://doi.org/10.3390/ph14020133 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 24

One strategy for increasing the potency while mitigating the side effects of platinum complexes is to exploit new compounds that operate on novel mechanisms [15,16]. In this respect, cationic monofunctional PtII complexes that contain only one labile ligand exhibit special anticancer activities in comparison with cisplatin analogues due to the changes in DNA-binding mode, cellular accumulation, and even the mechanism of action [17,18]. These complexes represent an alternative class of anticancer agents that violate the classical structure-activity relationships (SAR) of platinum complexes [15]. Their antineoplastic activity arises from diverse interactions with different biomolecules and displays a distinct spectrum of activity in favor of circumventing the drug resistance or side effects [19–22]. Pharmaceuticals 2021, 14, 133 DNA remains the major, if not the only, target for most2 of of 23 monofunctional PtII complexes. Nevertheless, the DNA-binding mode or process is different from that of cisplatin andOne its strategy analogues. for increasing Each the monofunctional potency while mitigating complex the side effects could of platinumform at most one covalent bond complexeswith the is toN7 exploit-guanine new compounds on the DNA that operate strands on novel rather mechanisms than [15two,16]. covalent In this Pt−DNA cross-links as respect, cationic monofunctional PtII complexes that contain only one labile ligand exhibit + + specialcisplatin anticancer does activities [23]. The in comparison earliest withprototype cisplatin analoguescomplexes due to[Pt(NH the changes3)3Cl] and [Pt(dien)Cl] (dien in= DNA-bindingdiethylenetriamine) mode, cellular accumulation,are thought and to even be theinactive mechanism towards of action [cancer17,18]. cells, since according to These complexes represent an alternative class of anticancer agents that violateII the classical structure-activitythe prevailing relationships view only (SAR) neutral of platinum and complexes square- [planar15]. Their Pt antineoplastic complexes with a pair of inert lig- activityands arises in a from cis diverse-configuration interactions with possess different anticancer biomolecules and activity displays a[6, distinct24,25]. However, the precon- spectrum of activity in favor of circumventing the drug resistance or side effects [19–22]. ceived belief was overturned by the finding that cis-[Pt(NH3)2(Am)Cl]+ (Am is an aromatic DNA remains the major, if not the only, target for most of monofunctional PtII complexes.N-heterocyclic Nevertheless, theamine) DNA-binding inhibited mode ortumor process iscells different in fromvitro that and of cisplatin leukemia (L1210 and P388) in andmouse its analogues. models Each [26], monofunctional where Pt complexII formed could stable form at mostPt–DNA one covalent adducts bond and the complex interca- with the N7-guanine on the DNA strands rather than two covalent Pt−DNA cross-links as + + cisplatinlated into does [ 23DNA.]. The earliest Further prototype studies complexes found [Pt(NH that3)3 Cl]aminoand [Pt(dien)Cl]or Am groups(dien could lose upon binding =to diethylenetriamine) DNA, thereby are achieving thought to be inactivea bifunctional towards cancer coordination cells, since according [27]. to the II prevailing view only neutral and square-planar Pt complexes with a pairII of inert ligands in a cis-configurationAfterwards, possess it was anticancer found activity that [ 6,the24,25 ].cationic However, Pt the preconceivedcomplex pyriplatin (Figure 2) only + beliefformed was overturned a monofunctional by the finding adduct that cis-[Pt(NH with3 )DNA2(Am)Cl] and(Am induced is an aromatic littleN distortion- in the DNA dou- heterocyclicble helix amine) upon inhibited binding tumor. In cells addition,in vitro and organic leukemia cation (L1210 andtransporters P388) in mouse (OCTs) were involved in its models [26], where PtII formed stable Pt–DNA adducts and the complex intercalated into DNA.cellular Further uptake studies foundand activity that amino [28 or Am,29]. groups SAR could studies lose upon indicated binding to that DNA, the steric hindrance of the therebypyridine achieving ligand a bifunctional played coordinationan important [27]. role in regulating the action of RNA polymerase II [30– Afterwards, it was found that the cationic PtII complex pyriplatin (Figure2) only formed32]. Phenanthriplatin a monofunctional adduct (Figure with DNA2) also and formed induced little monofunctional distortion in the DNAadducts with guanine bases as doublewell helixas duplex upon binding. DNA In once addition, the organic chloride cation ligand transporters lost. (OCTs) Phenanthr were involvediplatin-DNA adducts generate in its cellular uptake and activity [28,29]. SAR studies indicated that the steric hindrance of thesteric pyridine hindrance ligand played in anthe important major rolegroove in regulating of DNA the action and of thus RNA, polymerasestall the progression of RNA poly- IImerase [30–32]. Phenanthriplatin II on the damaged (Figure2 )DNA also formed templates monofunctional and inhibit adducts DNA with guanine polymerases [33]. This complex baseshas asa wellunique as duplex cytotoxic DNA once profile the chloride as it ligand was lost.7–40 Phenanthriplatin-DNA times more active adducts than cisplatin in many human generate steric hindrance in the major groove of DNA and thus, stall the progression of RNAcancer polymerase cell line II ons theand, damaged unlike DNA pyriplatin, templates and showed inhibit DNA an activity polymerases spectrum [33]. in the more extensive ThisNCI complex-60 panel has a unique of cell cytotoxic lines profile [34, as35]. it was Other 7–40 times monofunctional more active than cisplatin PtII complexes that suppressed in many human cancer cell lines and, unlike pyriplatin, showed an activity spectrum in theRNA more polymerase extensive NCI-60 II panel and of DNA cell lines synthesis [34,35]. Other, and monofunctional displayed Pt highII complexes cytotoxicity against cancer cells thatwere suppressed also reported RNA polymerase [36–39]. II and Yet DNA, this synthesis, is not andthe displayed whole story high cytotoxicity on the mechanism of action. More against cancer cells were also reported [36–39]. Yet, this is not the whole story on theII mechanismand more of action.studies More revealed and more that studies the revealed target that of the monofunctional target of monofunctional Pt complexes is not limited to PtorII complexes even relevant is not limited to DNA. to or even Therefore, relevant to DNA. the Therefore,established the established SARs no SARs longer fit them. This review II nowill longer introduce fit them. This some review representative will introduce some monofunctional representative monofunctional PtII complexes Pt published in the past 5 complexes published in the past 5 years or so and discuss their mechanism of action ifyears possible. or so and discuss their mechanism of action if possible.

FigureFigure 2. Chemical 2. Chemical structures structures of pyriplatin andof pyriplatin phenanthriplatin. and phenanthriplatin.

2. Fluorescent Monofunctional PtII Complexes DNA has been extensively studied as the ultimate cellular target of platinum complexes, while much of the mechanism of action still remains unknown. Although some small ions or molecules, amino acids, peptides, and proteins are thought to be implicated

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2. Fluorescent Monofunctional PtII Complexes Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 24 DNA has been extensively studied as the ultimate cellular target of platinum complexes, while much of the mechanism of action still remains unknown. Although some small ions or molecules, amino acids, peptides, and proteins are thought to be implicated inin thethe mechanism,mechanism, the the details details on on the the cellular cellular interactions interactions are are largely largely unclear. unclear. Therefore, Therefore, it isit ofis of great great significance significance to studyto study the the behavior behavior ofPt ofII PtcomplexesII complexes in cancerin cancer cells cells at the at the molecular molec- level.ular level. Tethering Tethering fluorophores fluorophores to the to PttheII centerPtII center of the of complexesthe complexes could could form form fluorescent fluores- molecules,cent molecules by this, by means this means the cellular the cellular location location of the complexes of the complexes could be could mapped be throughmapped fluorescencethrough fluorescence imaging. imaging. II DinuclearDinuclear PtPtII complex 1 incorporate aa fluorescentfluorescent anthraquinoneanthraquinone intercalatorintercalator inin thethe structurestructure (Figure(Figure3 ).3). Its Its major major merit merit is tois monitorto monitor the subcellularthe subcellular localization localization by fluorescence by fluores- microscopycence microscopy on account on account of the innateof the innate fluorescence fluorescence of the intercalator.of the intercalator.Complex Complex1 exhibited 1 ex- highhibited cytotoxicity high cytotoxicity in the U2-OS in the cell U line2-OS (the cell designation line (the ofdesignation U2-OS and of those U2- ofOS other and cellthose lines of appearedother cell hereafterlines appeared are listed hereafter in Appendix are listedA Table in A1Appendix at the end A ofTable the article) A1 at andthe end overcame of the resistancearticle) and in overcame the cisplatin-resistant resistance in the U2-OS/Pt cisplatin cell-resistant line. Their U2-OS/Pt cellular cell process line. Their in both cellular cell linesprocess was in similar, both cel whichl lines maywas besimilar, due to which the formation may be due of intercalativeto the formation DNA-adducts of intercalative that couldDNA- evadeadducts the that DNA could repair evade mechanism the DNA responsible repair mechanism for removing responsible the cisplatin for removing adducts [ 40the]. Thecisplatin fluorescence adducts indicated[40]. The fluorescence that 1 rapidly indicated entered that the U2-OS1 rapidly cells enter anded accumulatedthe U2-OS cells in theand nucleus, accumul therebyated in the reaching nucleus, the thereby biological reaching target the of thebiological Pt and target intercalating of the Pt moieties— and inter- DNAcalating [41 moieties,42]. The— PtDNA moiety [41,42]. was The excreted Pt moiety from was the cellexcreted via the from Golgi the apparatus,cell via the whileGolgi the weakly basic anthraquinone ligand accumulated in the Golgi complex, where it was apparatus, while the weakly basic anthraquinone ligand accumulated in the Golgi com- taken up by lysosomes and then transported to the cell surface. Interestingly, contrasting plex, where it was taken up by lysosomes and then transported to the cell surface. Inter- results were found in A2780 cells, implying that different cell lines may respond to Pt drugs estingly, contrasting results were found in A2780 cells, implying that different cell lines differently [41]. In cisplatin-resistant A2780 cells, the complexes were sequestered into may respond to Pt drugs differently [41]. In cisplatin-resistant A2780 cells, the complexes lysosomes and displayed cross-resistance with cisplatin. were sequestered into lysosomes and displayed cross-resistance with cisplatin.

FigureFigure 3.3. Chemical structures ofof complexescomplexes 11–‒55..

FluorescentFluorescent complexes 22 andand 33 (Figure(Figure 3)3) were were used used to to track track their their cellular cellular distribution distribu- tionvia detecting via detecting the fluorescence, the ﬂuorescence, thus providing thus providing new insights new insights into the into mechani the mechanismsm of action of action[43]. Complex [43]. Complex 3 is more3 is suitable more suitable for cellular for cellular imaging imaging than 2 than. Particularly,2. Particularly, in contrast in contrast to the torapid the rapidentry entryto cells to but cells ina butccessibility inaccessibility to the to nucleus the nucleus for the for ligand the ligand,, cationic cationic 3 entered3 entered the theHeLa HeLa cells cells slowly slowly and and mainly mainly accumulated accumulated in in the the nucleoli. nucleoli. It It b boundound to to the cytoplasmiccytoplasmic vacuoles, resulting in a different distribution pattern from that of neutral fluorescent Pt complexes. Complex 3 not only acted as a probe to trace its cellular behavior, but also induced non-apoptotic cell death. Similarly, complex 4 (Figure 3) realized the in vitro and vivo fluorescence imaging [44]. Its cellular uptake was much slower than that of the ligand

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vacuoles, resulting in a different distribution pattern from that of neutral fluorescent Pt complexes. Complex 3 not only acted as a probe to trace its cellular behavior, but also induced non-apoptotic cell death. Similarly, complex 4 (Figure3) realized the in vitro and vivo fluorescence imaging [44]. Its cellular uptake was much slower than that of the ligand and it could get into the nucleus, suggesting that the PtII center played an important role in reducing the uptake process and promoting its affinity for DNA. Complex 4 also exhibited preferential affinity for mitochondria. Another cytotoxic fluorescent complex 5 (Figure3) constructed by tethering a fluorophore thioflavin-T (ThT) derivative to the 3N-chelated PtII center was suitable for cellular imaging in living cells [45]. Fluorescence imaging showed that 5 was sequestrated in mitochondria and acidic lysosomes after slow entry to the cells. The finding provides new insights into the cellular distribution of positively-charged monofunctional PtII complexes. It should be noted that in analyzing the distribution of fluorescent complexes, a comparison with the distribution of free ligands is necessary so as to eliminate the false fluorescence emitted by the dissociated fluorophores.

3. Photoactive Monofunctional PtII Complexes The toxic side effects resulted from the non-specific accumulation of Pt anticancer agents hinder their broader application in clinical treatment. Photoactive Pt complexes offer an opportunity to develop new anticancer drugs responsive to light [46,47]. Photodynamic therapy (PDT) is a minimally invasive method that produces selective cytotoxicity to malignant tumor cells. It has been used to treat different tumors, such as bladder and prostate cancers [48]. The anticancer effect of PDT is achieved by killing cancer cells through 1 reactive oxygen species (ROS) such as singlet oxygen ( O2) produced by photosensitizers (PSs) under light irradiation [49]. Non-irradiated PSs generally have low dark toxicity, high 1 O2 quantum yield, and good cellular accessibility [50], while the irradiated one is strongly bioactive. It has been shown that the combination of Pt complexes with PSs could produce synergistic effects [6,51,52]. Porphyrins are representative PSs for PDT owing to the ring structure with 18 conjugated π electrons, which endow the compounds with photophysical properties and selective retention or accumulation in tumors due to preferential binding to low density lipoproteins [53,54]. The structure of porphyrin is susceptible to functionalization of sur- rounding substituents, especially the presence of metal complexes around or in the core could modify the local environment, improving the solubility or introducing specific func- tionalities [54,55]. In order to potentiate the action of these structures, conjugations with PtII complexes were tried. The isomeric tetra-cationic(pyridyl)porphyrin PtII complexes 6 and 7 (Figure4) possessed cytotoxicity against metastatic WM1366 cells under white-light irradiation, inducing apoptosis via the activation of caspase-3 and -9 and alteration of cell cytoskeleton actin [56]. In silico study indicated that these complexes could be employed to deliver drugs owing to the affinity to the N-terminal region of ApoB-100. Complex 8 (Figure4) showed an excellent photocytotoxicity (50 W LED light, 6 J cm−2, 1 30 min) due to the high O2 quantum yield, nuclear internalization, and a caspase-3- induced apoptosis with negligible dark toxicity [57]. Oxaliplatin was chosen as the phar- macophore since its DNA binding rate is faster than that of cisplatin. Moreover, it could improve the hydrophilicity and eliminate the formation of aggregates by increasing the electrostatic repulsion from charged functional groups [58]. Furthermore, 8 completely wiped out the tumor tissue in colon26 tumor-bearing mice. Similarly, the aqueous solubility, cellular uptake, and photophysical property of the tetraplatinated porphyrin complex 9 (Figure4) were improved by incorporating Pt II moieties [51], which directed the porphyrin to the nucleus and enhanced the nuclear Pt accumulation. The binding to DNA involves both covalent bonding with N7-guanine by PtII and intercalation by the porphyrin unit. Complex 9 demonstrated a promising photocytotoxicity with extremely high toxicity towards human cancer cell lines upon irradiation (6.95 J cm−2, 420 nm, 15 min, HeLa: Pharmaceuticals 2021, 14, 133 5 of 23

Pharmaceuticals 2021, 14, x FOR PEER REVIEW IC = 37 nM; A2780: IC = 21 nM; CP70: IC = 19 nM), and a phototoxic5 of 24 index up to 50 50 50 5000 in the cisplatin-resistant CP70 cell line.

Figure 4. Chemical structuresFigure of 4.complexesChemical 6 structures‒9. of complexes 6–9.

Despite the factDespite that porphyrin the fact that-based porphyrin-based Pt complexes have Pt complexes many advantages, have many the advantages, poor the poor solubility and solubilityaggregation and of aggregation porphyrins of affect porphyrins their cellular affect their uptake cellular and uptakelimit their and activ- limit their activities ities and applicationsand applications in vivo. Thus,in vivo water. Thus,-soluble water-soluble tumor-targeted tumor-targeted PS 10 (Figure PS 5) 10with(Figure a 5) with a porphyrin frameworkporphyrin containing framework Ga containingIII and PtII moieties GaIII and was PtII developedmoieties was [59]. developed Complex [1059 ]. Complex 10 1 is an efficient 1isO an2 generator efficient owingO2 generator to the heavy owing atom to the effect, heavy acidic atom effect,pKa, and acidic localization pKa, and localization in in cytosol. It showedcytosol. negative It showed dark negative cytotoxicity dark cytotoxicity due to the duelarger to hydrophilicity, the larger hydrophilicity, slower slower and and lower cellularlower uptake. cellular Moreover, uptake. Moreover, it exhibited it exhibitedremarkable remarkable photocytotoxicity photocytotoxicity and inter- and interaction action with DNA,with accumulated DNA, accumulated in tumor in prominently tumor prominently (tumor/muscle (tumor/muscle ratio > 9), and ratio inhib- > 9), and inhibited ited tumor growthtumor almost growth complet almostely completely over 2 weeks. over 2 No weeks. significant No significant systemic systemic toxicity toxicityin- including cluding weightweight loss and loss adverse and adverse reactions reactions were observed were observed.. 1 The low efficiencyThe lowof 1O efficiency2 generation of withinO2 generation the maximum within tissue the maximum penetrating tissue and bi- penetrating and ocompatible spectralbiocompatible window spectral (650–850 window nm) is (650–850another limitation nm) is another in addition limitation to the in additionaggre- to the aggre- IV gation and solubilitygation andof PSs solubility. SiIV phthalocyanines of PSs. Si phthalocyanines (SiPc), characterized (SiPc), characterized by reduced byaque- reduced aqueous aggregation and high 1O quantum yield when illuminated with tissue-penetrating far-red ous aggregation and high 1O2 quantum2 yield when illuminated with tissue-penetrating II IV far-red light, couldlight, solve could this solve problem this problem [60,61]. [A60 positively,61]. A positively-charged-charged PtII–SiIV phthalocya- Pt –Si phthalocyanine nine complex 11complex (Figure11 5)(Figure was selectively5) was selectively delivered delivered to cancer to cells cancer by the cells hyaluronic by the hyaluronic acid acid (HA) (HA) formulatedformulated nanoparticles nanoparticles with the withmediation the mediation of the CD44 of the receptor CD44 [62]. receptor The [nano-62]. The nanoparti- particles showedcles improved showed improvedaqueous solubility, aqueous solubility,specific uptake, specific photo uptake,-enhanced photo-enhanced cytotox- cytotoxicity icity (~1500-fold)(~1500-fold) and mitochondrial and mitochondrial accumulation accumulation in CD44-overexpressed in CD44-overexpressed breast cancer breast cancer cells over normal ones in red light (45 min, 660–680 nm, 5.5 ± 2.5 mW cm−2). Interestingly, cells over normal ones in red light (45 min, 660–680 nm, 5.5 ± 2.5 mW cm−2). Interestingly, the nanoconjugate delivered 11 only to cancer cells, which resulted in the generation of cytotoxic 1O2 and PtII species.

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Complexes 12 and 13 (Figure 5) presented a 25- and 7-fold enhancement, respectively, in cytotoxicity against HeLa cells at 1 μM under illumination with red light in comparison to those kept in the dark [63]. Both complexes demonstrated a potential to serve as DNA- targeting PDT agents. The PtII moieties lead the PDT moiety to approach DNA and execute red-light-induced oxidative damage, while the photoactive SiPc moiety endows the PtII units with a red-light-induced photochemical property that may lead to enhanced DNA

Pharmaceuticals 2021, 14, 133 platination. This design was expected to be superior over solo therapeutic modalities6 ofand 23 obtain drugs with improved activity and reduced side effects. The use of phthalocyanine could alleviate some limitations of PDT, however, the self-aggregation in aqueous media may affect its photosensitivity. In brief, the Pt–porphyrin or Pt–phthalocyanine conjugates maintainedthe nanoconjugate the intrinsic delivered properties11 only of an to cancerindividual cells, unit which in cancer resulted cells, in and the thus generation could act of 1 II ascytotoxic dual threatO2 andanticancer Pt species. agents.

Figure 5. Chemical structures of complexes 10–‒13.

PSsComplexes based on12 nonand-macrocyclic13 (Figure5) dyes presented were also a 25- used and 7-foldto design enhancement, conjugates respectively,for the com- binativein cytotoxicity effect of against PDT and HeLa inhibition cells at 1ofµ MDNA under transcription. illumination Complexes with red light14 and in 15 comparison (Figure 6) showedto those remarkable kept in the darkphotocytotoxicity [63]. Both complexes in visible demonstrated light (400−700 a nm, potential 10 J cm to−2 serve) to the as HaCaT DNA- II andtargeting MCF PDT-7 cells, agents. with Thethe PtIC50moieties being in leadthe nanomolar the PDT moiety level to, while approach they DNAwere almost and execute non- II toxicred-light-induced (IC50 > 80 μM) oxidative in the dark damage, [64]. whileComplex the photoactive14 was emissive SiPc and moiety showed endows significant the Pt localizationunits with a inred-light-induced the mitochondria photochemical and minor localization property that in may the endoplasmlead to enhancedic reticulum DNA platination.(ER), and hence This could design be was used expected for cellular to be imaging superior and over reducing solo therapeutic the drawbacks modalities associated and obtain drugs with improved activity and reduced side effects. The use of phthalocyanine could alleviate some limitations of PDT, however, the self-aggregation in aqueous media may affect its photosensitivity. In brief, the Pt–porphyrin or Pt–phthalocyanine conjugates

maintained the intrinsic properties of an individual unit in cancer cells, and thus could act as dual threat anticancer agents. PSs based on non-macrocyclic dyes were also used to design conjugates for the combinative effect of PDT and inhibition of DNA transcription. Complexes 14 and 15 (Figure6) showed remarkable photocytotoxicity in visible light (400 −700 nm, 10 J cm−2) to the HaCaT and MCF-7 cells, with the IC50 being in the nanomolar level, while they were almost nontoxic (IC50 > 80 µM) in the dark [64]. Complex 14 was emissive and showed Pharmaceuticals 2021, 14, x FOR PEER REVIEW 7 of 24

with bifunctional binding of nuclear DNA (nDNA) by Pt drugs, such as nuclear excision repair (NER).

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Figure 6. Chemical structures of complexes 14 and 15. Pharmaceuticals 2021, 14, x FOR PEER REVIEW 7 of 24

Cationicsignificant PS is helpful localization to promote in the cellular mitochondria accumulation and minor of anticancer localization agents in the and endoplasmic damage the reticulumcell membrane (ER), by and photo hence-induced could be ROS used in forsitu, cellular which imagingis considered and reducing as the main the drawbacks mechanism associatedtowith enhance bifunctional with the cellular bifunctional binding uptake of binding nuclear [65]. Complex of DNA nuclear (nDNA) 16 DNA (Figure (nDNA)by Pt 7) drugs, exhibited by Pt such drugs, dis astinct nuclear such as nuclearexcision anticancer cytotoxicityexcisionrepair (NER). repair against (NER). MCF-7, SGC-7901, A549, and HeLa cell lines via short time photoirradiation (532 nm, 3.5 mW cm−2, 5 min) [66]. It first accumulated on the surface of the cell membrane in the dark for its membrane-anchoring ability, and then acted as a PS, promoting the damage to the cell membrane in situ to increase its accumulation in tumor cells. Although the molecular mechanism was not studied, short time photoirradiation seems to play a key role in activating the complex. Lysosomes as special organelles are responsible for degrading and recycling extra- cellular materials via endocytosis and phagocytosis, and intracellular poisonous species via autophagy [67,68]. Growing evidence indicates that lysosomes are capable of isolating some Pt complexesFigureFigure 6. 6.toChemical Chemical reduce their structuresstructures contact of of complexes withcomplexes nDNA14 14,and andthus15 15 reducing. . the DNA-damaging effect [69]. Therefore, silencing Pt complexes in lysosomes and then activating them spe- cifically in the tumorCationicCationic tissue PSPS mightis is helpful helpful be a to methodto promote promote forthe improvingthe cellular cellular accumulationthe accumulation antitumor of activityof anticancer anticancer and agents agents and and alleviating sidedamagedamage effects. the the Complex cell cell membrane membrane 17 (Figure by by photo-induced photo 7) is -theinduced firstROS exampleROS in in situ, situ, of which photoactivewhich is is considered considered mono- as as the the main main functional PtmechanismmechanismII complex capable toto enhanceenhance of lysosomal thethe cellularcellular escape uptakeuptake [70]. [ 65[65]. It]. was Complex Complex sequestered16 16(Figure (Figure in lysosomes7 )7) exhibited exhibited distinct distinct via endocytosisanticanceranticancer and showed cytotoxicity cytotoxicity low cytotoxicity against against MCF-7, MCF to both-7, SGC-7901, SGC normal-7901, and A549, A549 tumor, and and cells HeLa HeLa with cell cellout lines lines pho- via via short short time time −2 toirradiation.photoirradiationphotoirradiation Interestingly, it(532 escaped(532 nm, nm, 3.5from 3.5 mW mW the cm lysosomescm−2,, 55 min)min) to [[66]. 66the]. nucleus ItIt firstfirst accumulatedaccumulated upon short- ontimeon the the surface surface of of photoirradiationthethe cell cell (532 membranemembrane nm, 3.5 mW inin thecmthe− dark2dark, 5 min) forfor its dueits membrane-anchoringmembrane to the photoinduced-anchoring ability,abilityability, to and and generate then then acted acted as as a a PS, PS, ROS. Apart frompromotingpromoting damaging the the damage damagelysosomes to to the tothe release cell cell membrane membrane 17 into the in in cytosol situ situ to toincrease anincreased nucleus, its its accumulation accumulation ROS also in in tumor tumor decreased intracellularcells.cells. AlthoughAlthough GSH the thelevels molecularmolecular to impede mechanismmechanism its deactivation waswas notnot in studied, studied,the cytosol shortshort and time time further photoirradiation photoirradiation increased itsseems seemsaccessibility to to play play to a a key nDNAkey role role favorable in in activating activating for the the the antitumor complex. complex. activity. Lysosomes as special organelles are responsible for degrading and recycling extra- cellular materials via endocytosis and phagocytosis, and intracellular poisonous species via autophagy [67,68]. Growing evidence indicates that lysosomes are capable of isolating some Pt complexes to reduce their contact with nDNA, thus reducing the DNA-damaging effect [69]. Therefore, silencing Pt complexes in lysosomes and then activating them spe- cifically in the tumor tissue might be a method for improving the antitumor activity and alleviating side effects. Complex 17 (Figure 7) is the first example of photoactive monofunctional PtII complex capable of lysosomal escape [70]. It was sequestered in lysosomes via endocytosis and showed low cytotoxicity to both normal and tumor cells without photoirradiation. Interestingly, it escaped from the lysosomes to the nucleus upon short-time −2 Figure 7. Chemicalphotoirradiation Figurestructures 7. Chemical of complexes(532 nm, structures 3.5 16 andmW of 17 complexescm. , 5 min)16 dueand 17to. the photoinduced ability to generate ROS. Apart from damaging lysosomes to release 17 into the cytosol and nucleus, ROS also Pt complexesdecreasedLysosomes comb intracellularined as with special PSs GSH organellesmay levels exhibit to are impede synergistic responsible its deactivation effects, for degrading but mostin the andof cytosol them recycling and further extra- are limited tocellularincreased Pt–porphyrin materials its accessibility conjugates. via endocytosis to nDNAReplacing and favorable phagocytosis, porphyrin for the with andantitumor other intracellular PSs activity. is another poisonous species way to developvia autophagyeffective PDT [67 ,agents.68]. Growing A series evidence of DNA indicates-binding that PtII– lysosomestriphenylamine are capable com- of isolating plexes were somedeveloped Pt complexes as potential to reduce PDT anticancer their contact agents with [71 nDNA,–74]. The thus fluorogens reducing the π-con- DNA-damaging jugated triphenylamines,effect [69]. Therefore, owing to silencing two-photon Pt complexes absorption in and lysosomes aggregation and then induced activating emis- them specif- sion (AIE) properties,ically in the are tumor used as tissue fluorescent might probes be a method or theranostic for improving agents [75]. the antitumor In order to activity and improve thealleviating PDT efficiency side of effects. the conjugates Complex and17 (Figuresystematically7) is the investigate first example the ofanticancer photoactive monofunctional PtII complex capable of lysosomal escape [70]. It was sequestered in lysosomes via endocytosis and showed low cytotoxicity to both normal and tumor cells without photoirradiation. Interestingly, it escaped from the lysosomes to the nucleus upon short-time photoirradiation (532 nm, 3.5 mW cm−2, 5 min) due to the photoinduced ability to generate ROS. Apart from damaging lysosomes to release 17 into the cytosol and nucleus, ROS also decreased intracellular GSH levels to impede its deactivation in the cytosol and further Figure 7. Chemical structures of complexes 16 and 17. increased its accessibility to nDNA favorable for the antitumor activity. Pt complexes combined with PSs may exhibit synergistic effects, but most of them are Pt complexes combined with PSs may exhibit synergistic effects, but most of them limited to Pt–porphyrin conjugates. Replacing porphyrin with other PSs is another way to are limited to Pt–porphyrin conjugates. Replacing porphyrin with other PSs is another develop effective PDT agents. A series of DNA-binding PtII–triphenylamine complexes way to develop effective PDT agents. A series of DNA-binding PtII–triphenylamine com- were developed as potential PDT anticancer agents [71–74]. The fluorogens π-conjugated plexes were developed as potential PDT anticancer agents [71–74]. The fluorogens π-con- triphenylamines, owing to two-photon absorption and aggregation induced emission jugated triphenylamines, owing to two-photon absorption and aggregation induced emission (AIE) properties, are used as fluorescent probes or theranostic agents [75]. In order to improve the PDT efficiency of the conjugates and systematically investigate the anticancer

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(AIE) properties, are used as fluorescent probes or theranostic agents [75]. In order to improve the PDT efficiency of the conjugates and systematically investigate the anti- SAR, trinuclearcancer Pt– SAR,triphenylamine trinuclear Pt–triphenylamineisomers 18−21 (Figure isomers 8) were18− developed21 (Figure8 [76].) were Com- developed [ 76]. plexes 18 andComplexes 19 exhibited18 andmuch19 betterexhibited PDT much activity better than PDT complexes activity than 20 and complexes 21 owing20 toand 21 owing 1 the redder absorptionto the redder and absorption emission wavelength, and emission hi wavelength,gher cellular higheruptake cellularand 1O2 uptakequantum and O2 quan- yield, strongertum DNA yield,-binding stronger and DNA-binding photo-cleavage and ability. photo-cleavage In addition, ability. complexes In addition, 18 and complexes 18 19 mainly accumulatedand 19 mainly in the accumulated nucleus, while in the complexes nucleus, while 20 and complexes 21 distributed20 and mainly21 distributed in mainly the cytoplasm.in theParticularly, cytoplasm. complex Particularly, 19 elicit complexed DNA19 damageelicited responses, DNA damage arrest responses,ed the cell arrested the cycle in the G2/Mcell cycle phase in, theand G2/M led to phase,apoptosis and in led cancer to apoptosis cells upon in cancerlight irradiation cells upon at light 425 irradiation −2 nm (40 mW cmat 425−2, 15 nm min) (40. M mWoreover, cm it, 15exhibited min). Moreover, significant it PDT exhibited effect on significant HeLa xenograft PDT effect- on HeLa bearing micexenograft-bearing, including reduction mice, in including the tumor reduction volume and in the cell tumor death volume in tumor and sections, cell death in tumor but showed sections,no noticeable but showed side effects no noticeable on body weight side effects and major on body organs weight. and major organs.

Figure 8. Chemical structuresFigure 8. ofChemical complexes structures 18‒21. of complexes 18–21.

4. Targeted Monofunctional PtII Complexes 4. Targeted Monofunctional PtII Complexes Although Pt-based drugs play an important part in cancer therapeutic regimens, their widespreadAlthough use is still Pt-basedlimited by drugs the severe play toxic an important side effects part arising in cancer from the therapeutic lack of regimens, selectivity fortheir cancer widespread cells. To overcome use is still this limited defect, by thecancer severe-targeted toxic sidePt complexes effects arising are de- from the lack veloped. Theof targeting selectivity group(s) for cancer in such cells. complexes To overcome could this direct defect, the Pt cancer-targeted warheads to cancer Pt complexes are cells by interactingdeveloped. with The the targeting receptors group(s) overexpressed in such complexeson the cell couldsurface direct [77], the or Ptdirect warheads to to cancer the tumor ascells a whole by interacting through the with interaction the receptors with the overexpressed tumor-related on cell the cellsurface surface markers [77], or direct to such as antigensthe tumor or receptors as a whole [78]. Targeting through the could interaction also be achieved with the at tumor-related the subcellular cell level, surface markers allowing Pt suchto be asdirected antigens to or specific receptors organelles [78]. Targeting to elicit could biological also be effects achieved [6,78]. at theHerein subcellular, level, allowing Pt to be directed to speciﬁc organelles to elicit biological effects [6,78]. Herein, we we particularly focus on monofunctional PtII complexes designed for these purposes. particularly focus on monofunctional PtII complexes designed for these purposes. Taking osteosarcoma (OS) as an example, which is a primary malignant bone tumor Taking osteosarcoma (OS) as an example, which is a primary malignant bone tumor severely threatens the life of adolescents [79]. Owing to the peculiar tumor sites (knee joint severely threatens the life of adolescents [79]. Owing to the peculiar tumor sites (knee joint and appendicular skeleton) and lack of knowledge about driving oncogenes, as well as and appendicular skeleton) and lack of knowledge about driving oncogenes, as well as insufficient drug concentration in the tumor site, OS is extremely difficult to treat [80,81]. Cisplatin is ineffective for OS due to its poor accessibility and severe systemic toxicity [82]. The coordination of phosphonate groups with Ca2+ ions endows bisphosphonates with a

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Pharmaceuticals 2021, 14, x FOR PEER REVIEW 9 of 24 insufficient drug concentration in the tumor site, OS is extremely difficult to treat [80,81]. Cisplatin is ineffective for OS due to its poor accessibility and severe systemic toxicity [82]. The coordination of phosphonate groups with Ca2+ ions endows bisphosphonates with a special affinityaffinity for hydroxyapatitehydroxyapatite in the bonebone matrixmatrix [[83].83]. Complexes 22 and 23 (Figure(Figure9 9)) bearing a a bone-targeting bone-targeting bisphosphonate bisphosphonate moiety moiety exhibited exhibited potential potential selectivity selectivity for OS for [ 84 OS]. The[84]. cytotoxicityThe cytotoxicity of cisplatin-derived of cisplatin-derived22 was 22 was higher higher than than that that of oxaliplatin-derived of oxaliplatin-derived23 towards23 towards the the U2-OS U2-OS cells. cells. Bisphosphonate Bisphosphonate also also improved improved the the lipophilicity lipophilicity andand cellularcellular uptake of thethe complexes.complexes. Lipophilic 24 (Figure 99)) waswas optimizedoptimized toto maintainmaintain thethe bone-bone- targetingtargeting property as as well well as as to to minimize minimize the the reactivity reactivity of ofthe the PtII Pt centerII center in order in order to de- to decreasecrease the the systemic systemic toxicity toxicity [85]. [85]. Unlike Unlike complexes complexes 2222 andand 2323,, the the molecular mechanismmechanism of complexcomplex 24 involvesinvolves both both DNA DNA binding binding and and mevalonate mevalonate pathway pathway.. Its Its acute acute toxicity toxicity is is7-fold 7-fold lower lower than than that that of cisplatin. of cisplatin. The Theintroduction introduction of bisphosphonate of bisphosphonate provides provides a new a newpossibility possibility to overcome to overcome the ineffectiveness the ineffectiveness and systemic and systemic toxicity toxicity of Pt drugs of Pt drugs for the for treat- the treatmentment of OS of. OS.

Figure 9. Chemical structures of complexes 2222–‒2424..

Targeting thethe whole whole tumor tumor is is based based on on the the specific specific expression expression of some of some receptors receptors or anti- or gensantigens on the on surfacethe surface of tumor of tumor cells. cells. Tumor-associated Tumor-associated receptors receptors are wellare well documented documented in the in literature,the literature for, example,for example, transferrin, transferrin, selectins, selectins, integrins, integrins, folate folate receptor, receptor, glucose glucose transporter trans- (GLUT),porter (GLUT), galectins, galectins, hyaluronic hyaluronic acid receptors, acid receptors, and the and asialoglycoprotein the asialoglycoprotein receptor receptor [6,86]. Targeting[6,86]. Targeting these receptors these receptors could selectivelycould selectively deliver deliver a cytotoxic a cytotoxic agent agent to cancer to cancer cells. cells Inte-. grinsIntegrins are heterodimericare heterodimeric transmembrane transmembrane cell adhesioncell adhesion glycoproteins, glycoproteins, which which play play a key a rolekey inrole enhancing in enhancing migration, migration, invasion, invasion, and and proliferation proliferation of cancer of cancer cells, cells, and and even even are are linked linked to II tumorto tumor angiogenesis angiogenesis [87 [87].]. The The synthesis synthesis and and biological biological profile profile of of a a Pt PtII-c(RGDyK)-c(RGDyK) conjugateconjugate 25 (Figure(Figure 1010)) forfor integrin-targetedintegrin-targeted PDTPDT hashas beenbeen reported.reported. ComplexComplex 2525 waswas moderatelymoderately cytotoxic toward towardss six six cancer cancer cell cell lines lines with with different different levels levels of integrin of integrin expression expression [88]. [ 88It ].was It 1 was taken up rapidly by receptor-mediated endocytosis and generated1 O2 efficiently upon taken up rapidly by receptor-mediated endocytosis and generated O2 efficiently upon irra- irradiation, thus showing enhanced anticancer activity as a targeted PDT agent. diation, thus showing enhanced anticancer activity as a targeted PDT agent. Angiogenesis is an important process required for the development of new blood Angiogenesis is an important process required for the development of new blood ves- vessels, and is also crucial for tumorigenesis, tumor growth, survival, and metastasis. In the sels, and is also crucial for tumorigenesis, tumor growth, survival, and metastasis. In the case of tumor-induced angiogenesis, transmembrane receptors such as integrins (αvβ3 and case of tumor-induced angiogenesis, transmembrane receptors such as integrins (αvβ3 and αvβ5) are highly expressed, which have a very high affinity for peptides containing RGD αvβ5) are highly expressed, which have a very high affinity for peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) sequences. In this regard, complex 26 (Figure 10) (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) sequences. In this regard, complex 26 (Figure 10) with dual antiangiogenic and antitumor activity was a non-cytotoxic compound with with dual antiangiogenic and antitumor activity was a non-cytotoxic compound with IC50 IC50 >100 µM in different cancer cell lines (± αvβ3 and αvβ5 integrin receptors), while >100 μM in different cancer cell lines (± αvβ3 and αvβ5 integrin receptors), while showing showing the antiangiogenic activity in HUVECs at sub-cytotoxic concentrations [89], which the antiangiogenic activity in HUVECs at sub-cytotoxic concentrations [89], which exem- plified the design of angiogenesis inhibitors through conjugating a metallodrug with antiangiogenic activity to a cyclic RGD-containing peptide or a peptidomimetic analogue.

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Pharmaceuticals 2021,, 14,, xx FORFOR PEERPEER REVIEWREVIEW 10 of 24 exempliﬁed the design of angiogenesis inhibitors through conjugating a metallodrug with antiangiogenic activity to a cyclic RGD-containing peptide or a peptidomimetic analogue.

FigureFigure 10.10. ChemicalChemical structuresstructures ofof complexescomplexes 2525 andand 2626...

TargetingTargeting angiogenesis provides provides an an alternative alternative direction direction for for tumor tumor-targeting--targetingtargeting therapytherapy therapy[[90].].[ However,90]. However, some some complexes complexes do not do possess not possess a specific a specific targeting targeting group, group, but still but show still showantiangiogenic antiangiogenic activity. activity. For example, For example, dinuclearinuclear dinuclear complexescomplexes complexes 27–29 (Figure27(Figure–29 (Figure 11)) werewere 11) foundfound were foundtoto interactinteract to interact withwith thethe with phosphatephosphate the phosphate backbone,backbone, backbone, formingforming forming Pt--DNA Pt-DNA adducts adducts with a minor with a groove minor groovecovering covering [91].]. TheseThese [91]. complexes,complexes, These complexes, particularlyparticularly particularly complex complex 27,, areare 27potentialpotential, are potential chemotherapeuticschemotherapeutics chemothera- peuticswith anticancer with anticancer and antiangiogenic and antiangiogenic activities, activities, and no tox andicicno effectseffects toxic atat effects thethe desireddesired at the desiredconcen-concen- concentration.tration.tration. TheThey overc Theyame overcame cisplatin cisplatin resistance resistance in the zebrafish in the– zebrafish–mousemouse melanoma melanoma xenograft xenograftmodel and model effectively and effectivelyblocked tumortumor blocked neovascularizationneovascularization tumor neovascularization andand melanomamelanoma and melanomacellcell metastasis.metastasis. cell metastasis.The activation The of activation these complexes of these complexesmay result mayfrom result theirir frompositivepositive their chargecharge positive (+4)(+4) charge atat thethe (+4) physi-physi- at theological physiological conditions conditions and affinity and for affinity DNA, heparan for DNA, sulphate heparan (HS) sulphate,, and enzyme (HS), and heparanase enzyme heparanase(HPSE).(HPSE). ItIt isis (HPSE). worthworth notingnoting It is worth thatthat notingthethese complexes that these complexesshowed no showed sign of cardiovascular no sign of cardiovascu- toxicity lar toxicity such as pericardial edema or disturbed heart beat rate, and liver toxicity such as such as pericardial edema or disturbed heartt beatbeat rate,rate, and liverliver toxicitytoxicity such as liverliver ne-ne- liver necrosis, liver size change or reduced yolk absorption, which are the major obstacles crosis, liver size change or reduced yolk absorption, which are thethe majormajor obstaclesobstacles limitinglimiting limiting the long-term application of clinical anticancer drugs. thethe longlong--termterm application of clinical anticancer drugs.

FigureFigure 11.11. ChemicalChemical structuresstructures ofof complexescomplexes 2727–‒2929...

Organelle-targetingOrganelle--targetingtargeting anticanceranticanceranticancer agentsagentsagents addadd aa newnew dimensiondimension toto thethe discovery and de- velopmentvelopment of of Pt Pt drug drug candidates. candidates. Among Among different different organelles, organelles, mitochondria mitochondria have receivedhave re- muchceived attention much attention in recent in years.recent Theyears. oxidative The oxidative phosphorylation phosphorylation (OXPHOS) (OXPHOS)(OXPHOS) and glycolysis and gly- incoly mitochondriasis in mitochondria offer nutrients offer nutrients and energy and energy to cancer to cancer cells for cells occurrence, for occurrence, growth, growth and,, transformationand transformation [92,93 [[92].,, Nevertheless,93].]. Nevertheless,Nevertheless, unlike unlikeunlike normal normalnormal cells, cells,cells, most mostmost cancer cancercancer cells cell preferentiallys preferen- use aerobic glycolysis as the metabolic pathway for glucose, which is accompanied by a tiallytially useuse aerobicaerobic glycolysisglycolysis asas thethe metabolicmetabolic pathwaypathway forfor glucose,glucose, whichwhich isis accaccompanied high rate of glucose consumption and lactate production, even when oxygen is available by a high rate of glucose consumption and lactate production, even when oxygen is avail- for OXPHOS [94–96]. This abnormal energy metabolism process involves many proteins able for OXPHOS [[94–96].]. ThisThis abnormalabnormal energyenergy metabolismmetabolism processprocess involvesinvolves manymany pro-pro- and enzymes, thus providing potential targets for the design of anticancer drugs and teinsteins andand enzymes,enzymes, thusthus providing potential targets for the design of anticancer drugs and overcoming the drug resistance. overcominging thethe drug resistance. ItIt isis generally believed that nDNA is the primary target of Pt--based anticancer drugs, and the resistance to Pt agents mainly result from thethe extensive repair of Pt--DNA adducts

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It is generally believed that nDNA is the primary target of Pt-based anticancer drugs, and the resistance to Pt agents mainly result from the extensive repair of Pt-DNA adducts byby thethe activation activation of of DNA DNA repair repair mechanisms mechanisms in tumorin tumor cells cells [97 –[9799].–99 Whereas,]. Whereas, mitochondria mitochon- containdria contain their their own own cyclic cyclic mitochondrial mitochondrial DNA DNA (mtDNA), (mtDNA which), which is is more more vulnerable vulnerable to to damagedamage than nDNA due due to to the the lack lack of of histone histone protection protection and and proximity proximity to the to theROS ROS pro- productionduction sitesite [100 [,100101,].101 Therefore,]. Therefore, mtDNA mtDNA is a potential is a potential target targetfor potentiating for potentiating the activity the activityof anticancer of anticancer drugs. drugs.A cationic A cationic naphthalimide naphthalimide-modified-modified complex complex 30 (Figure30 (Figure 12) not 12) only not onlycaused caused severe severe nDNA nDNA damage damage but but also also induced induced the the mtDNA mtDNA lesion lesion and regulated regulated the the downstreamdownstream gene gene expression expression of of mtDNA-encoded mtDNA-encoded proteins proteins [102 [102]. Moreover,]. Moreover, it disturbed it disturbed the physiologicalthe physiological process process of mitochondria of mitochondria by reducing by reducing the mitochondrial the mitochondrial membrane membrane potential po- (MMP)tential (MMP) and promoting and promoting the generation the generation of ROS. of DinuclearROS. Dinuclear complex complex31 (Figure 31 (Figure 12) was 12) composedwas composed of IrIII ofand IrIII PtandII moieties.PtII moieties It accumulated. It accumulated in the in the mitochondria mitochondria by aby rate a rate of up of toup 76%to 76% with with an energy-independent an energy-independent uptake uptake mechanism mechanism [103]. The[103 complex]. The complex exhibited exhibited strong antitumorstrong antitumor activity activity towards towards A549R cisplatin-resistant A549R cisplatin-resistant cancer cells cancer and cells damaged and damaged the mtDNA the severely.mtDNA severely Further,. Further, it disrupted it disrupted the mitochondrial the mitochondrial function, function, resulted resulted in a loss in ofa loss MMP, of depletedMMP, depleted ATP, and ATP, finally and induced finally induced necrosis necrosis to cancer to cells. cancer All cells. these All findings these findings suggest thatsug- mtDNA-targetedgest that mtDNA- Pttargeted complexes Pt complexes are potential are antitumorpotential antitumor agents against agents cisplatin-resistant against cisplatin- cancerresistant cells. cancer cells.

FigureFigure 12.12. ChemicalChemical structuresstructures ofof complexescomplexes30 30and and31 31..

Recently,Recently, we we investigated investigated the the anticanceranticancer mechanismmechanism ofof threethree mitochondrion-targetedmitochondrion-targeted PtPtIIII complexescomplexes32 32−−3434 (Figure(Figure 13 13)) from from the the perspective perspective of DNAof DNA damage, damage, energy energy metabolism, metabo- andlism SAR, and [SAR104]. [104 Among]. Among them, them, complex complex32 exhibited32 exhibited greater greater inhibitory inhibitory activity activity on on the the A549A549 cellscellsthan than cisplatincisplatin in vitro and vivo. Moreover, Moreover, it it not not only only combined combined with with nDNA nDNA in ina monodentate a monodentate manner manner and and damaged damaged mtDNA, mtDNA, but butalso also inhibited inhibited glycolysis glycolysis of cancer of cancer cells, cells,affected affected the structure the structure and andfunct functionion of mitochondria, of mitochondria, resulting resulting in an in anabnormal abnormal process process of ofmitochondrial mitochondrial OXPHOS OXPHOS and and tricarboxylic tricarboxylic acid acid cycle. cycle. In vivoIn vivo studiesstudies showed showed that that as the as thetumor tumor shr shrank,ank, the thebody body weight weight of 32 of-treated32-treated mice mice also also reduce reduced,d, which which may may be due be due to the to themitochondrion mitochondrion-disrupting-disrupting effect. effect. Moreover Moreover,, most most of the of thePt accumulated Pt accumulated in the in theliver liver and andkidneys, kidneys, implying implying that thatthe cellular the cellular uptake uptake of 32 ofmay32 maybe mediated be mediated by organic by organic cation cation trans- Pharmaceuticals 2021, 14, x FOR PEER REVIEW 12 of 24 transporters,porters, which which are primarily are primarily expressed expressed in these in organs. these organs. This study This provides study provides new insights new insightsinto the intomechanism the mechanism of action of for action Pt anticancer for Pt anticancer drugs. drugs. Another mitochondrion-targeted complex 35 (Figure 13) that modified by triphenylphosphonium can modulate signaling pathways relevant to cancer bioenergetics [105]. It enhanced cytotoxicity against cisplatin-insensitive Caov-3 cells, exerted inhibition to mitochondrial thioredoxin reductase (TrxR), damaged mitochondrial morphology and function, destroyed both respiratory and glycolytic metabolisms, and induced cancer cells to enter into a hypometabolic state. The results highlight that targeting redox homeostasis and modulating metabolic pathways could effectively improve the anticancer effect.

FigureFigure 13.13. ChemicalChemical structuresstructures ofof complexescomplexes 3232–‒3535..

In order to overcome the shortcomings of classic Pt drugs, extensive research has been initiated to search for new targets other than DNA. Enzymes play vital roles in almost all physiological and pathophysiological processes, and have long been considered as drug targets [106]. It is estimated that more than 47% of drugs target enzymes [107]. Therefore, enzyme inhibition could be a significant and alternative mechanism for Pt- based anticancer drugs. Protein tyrosine phosphatases (PTPs), a superfamily of enzymes, participate in the regulation of the intracellular signal transduction pathway by removing the phosphate groups from proteins [108]. Dysregulated activities of PTPs are related to the pathogenesis of many human diseases such as cancers, diabetes, and autoimmune diseases [108,109]. Complex 36 (Figure 14) displayed an antiproliferative activity against MCF-7 cells superior to cisplatin [110]. It selectively inhibited PTP1B, thus significantly influenced the cellular phosphorylation level and further the intracellular signal transduction pathway, which is distinctly different from the DNA-damaging mechanism for cisplatin, thereby providing a new clue for designing Pt-based anticancer drugs. Hexokinase is the first rate-limiting enzyme in the glycolytic pathway, catalyzing the production of glucose-6-phosphate from glucose [111]. In normal cells, hexokinase iso- zymes have low transcriptional expression levels and each of them has tissue specificity, while as a key enzyme of glycolysis, hexokinase is widely and highly expressed in cancer cells, which not only promotes aerobic glycolysis, but also increases the resistance to cell death signals [112]. Complexes 37−39 (Figure 14), anchoring lonidamine (an inhibitor of hexokinase) to the PtII center, could selectively reduce the bioenergetics of cancer cells [113]. Particularly, 39 showed higher cytotoxicity than cisplatin against MDA-MB-231 cells (9.3 μM), caused significant damage to mtDNA, and disrupted mitochondrial bioenergetics. These complexes perturbed the signal pathways related to cell death, including DNA damage, the metabolic process, and transcription regulatory activity.

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Another mitochondrion-targeted complex 35 (Figure 13) that modified by triphenylphosphonium can modulate signaling pathways relevant to cancer bioenergetics [105]. It enhanced cytotoxicity against cisplatin-insensitive Caov-3 cells, exerted inhibition to mitochondrial thioredoxin reductase (TrxR), damaged mitochondrial morphology and function, destroyed both respiratory and glycolytic metabolisms, and induced cancer cells to enter into a hypometabolic state. The results highlight that targeting redox homeostasis and modulating metabolic pathways could effectively improve the anticancer effect. In order to overcome the shortcomings of classic Pt drugs, extensive research has been initiated to search for new targets other than DNA. Enzymes play vital roles in almost all physiological and pathophysiological processes, and have long been considered as drug targets [106]. It is estimated that more than 47% of drugs target enzymes [107]. Therefore, enzyme inhibition could be a significant and alternative mechanism for Pt-based anticancer drugs. Protein tyrosine phosphatases (PTPs), a superfamily of enzymes, participate in the regulation of the intracellular signal transduction pathway by removing the phosphate groups from proteins [108]. Dysregulated activities of PTPs are related to the pathogenesis of many human diseases such as cancers, diabetes, and autoimmune diseases [108,109]. Complex 36 (Figure 14) displayed an antiproliferative activity against MCF-7 cells superior to cisplatin [110]. It selectively inhibited PTP1B, thus significantly influenced the cellular phosphorylation level and further the intracellular signal transduction pathway, which is Pharmaceuticals 2021, 14, x FOR PEERdistinctly REVIEW different from the DNA-damaging mechanism for cisplatin, thereby providing13 of 24 a

new clue for designing Pt-based anticancer drugs.

Figure 14. ChemicalChemical structures structures of of complexes complexes 3636‒39–39. .

TelomeraseHexokinase is is present the first in the rate-limiting majority (85 enzyme–90%) of in cancer the glycolytic cells but is pathway, undetectable catalyzing in thenormal production cell lines, of which glucose-6-phosphate is restricted by the from level glucose of hTERT [111 and]. Inc-myc normal proteins cells, [114 hexokinase,115]. isozymesComplexes have 40−41 low (Figure transcriptional 15) induced expression apoptosis in levels the NCI and-H460 each cells of them via in hashibiting tissue the specificity,telomerase while and as adisrupting key enzyme the offunction glycolysis, of mitochondria hexokinase at is 0.89 widely and 0.10 and μM, highly respectively expressed in cancer[116,117 cells,]. In particular, which not 41 only significantly promotes inhibit aerobiced glycolysis,the growth of but tumor also in increases NCI-H460 the tumor resistance- tobearing cell death mice with signals the tumor [112]. growth Complexes inhibition37−39 rate(Figure (TGI) of 14 40.),7% anchoring and no obvious lonidamine toxicity (an. in- hibitorComplex of hexokinase) 42 (Figure to 15 the) containing PtII center, a couldjatrorrhizine selectively derivative reduce also the exhibited bioenergetics a remark- of cancer cellsable antitumor [113]. Particularly, activity and39 showedlower general higher toxicity cytotoxicity in vitro than and cisplatin vivo compar againsted to MDA-MB-231 cisplatin cells[118].(9.3 It displayedµM), caused high significant selectivity damagefor HeLa to cells mtDNA, (IC50 = and1.00 disrupted± 0.17 nM) mitochondrial by targeting p53 bioenergetics.and telomerase, These complexesand showed perturbed green luminesce the signalnce. In pathways addition, relatedit caused to mitochondrial cell death, including and DNA damage, and the metabolicinduced a process,high rate and of apoptosis transcription even regulatoryat a low dose activity. of 1.00 nM. The HeLaTelomerase tumor inhibition is present rate in (TIR) the majorityof 42 (48.8 (85–90%)%) was even of cancer higher cells than but that is undetectable of cisplatin in (35.2%). The low systemic toxicity of 42 is quite impressive, in that the body weight of the normal cell lines, which is restricted by the level of hTERT and c-myc proteins [114,115]. treated mice (mstart = 18.6 ± 0.5 g, mend = 20.1 ± 0.5 g) was hardly affected as compared with the control group (mstart = 18.7 ± 1.2 g, mend = 20.7 ± 1.4 g). Similarly, complex 43 (Figure 15) exerted cytotoxicity mainly via inhibiting telomerase by interaction with the c-myc quadruplex and disruption of the mitochondrial function [119]. The complex exhibited selective cytotoxicity to T-24 cells.

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Complexes 40−41 (Figure 15) induced apoptosis in the NCI-H460 cells via inhibiting the telomerase and disrupting the function of mitochondria at 0.89 and 0.10 µM, respectively [116,117]. In particular, 41 signiﬁcantly inhibited the growth of tumor in NCI- Pharmaceuticals 2021, 14, x FOR PEERH460 REVIEW tumor-bearing mice with the tumor growth inhibition rate (TGI) of 40.7%14 of and 24 no

obvious toxicity.

FigureFigure 15. Chemical structures structures of of complexes complexes 4040‒43–43. .

5. MiscellaneousComplex 42 M(Figureonofunctinoal 15) containing PtII Complexes a jatrorrhizine derivative also exhibited a re- markableGenerally, antitumor Pt drugs activity induce and cancer lower cell general death by toxicity interferingin vitro withand DNA vivo synthesis compared or to cisplatincausing chemical [118]. It damage displayed to DNA, high which selectivity is mainly for HeLa manifested cells (IC by50 apoptosis.= 1.00 ± However,0.17 nM) by targetingaccumulating p53 evidences and telomerase, indicate andthat showedPt drugs greenmay have luminescence. other molecular In addition, targets in itaddi- caused mitochondrialtion to DNA, which and DNAcan induce damage, cell death and inducedthrough anon high-apoptotic rate of pathways, apoptosis such even as at au- a low dosetophagy, of 1.00 necrosis, nM. The and HeLa even tumorimmunogenicity inhibition [ rate105,120 (TIR)–123 of].42 Complexes(48.8%) was 44–46 even (Figure higher 16) than thatshowed of cisplatin a dose-dependent (35.2%). Theantiproliferative low systemic activity toxicity in ofthe42 A2780is quite cells, impressive, with the cytotoxi- in that the bodycity order weight of 44 of < the45 < treated46, by a micecombinative (mstart =apoptotic 18.6 ± 0.5mechanism g, mend involving= 20.1 ± 0.5mitochondrial g) was hardly affectedand autophagic as compared pathways with [124 the]. control Complex group 47 (Figure (mstart =16 18.7) not± only1.2 g, initiated mend = a 20.7 series± 1.4 of g). Similarly,events associated complex with43 (Figuremitochondrial 15) exerted dysfunction, cytotoxicity but also mainly induced via inhibitingan apparent telomerase ER stress by interactionthrough the with ROS the release c-myc and quadruplex TrxR inhibition and disruption [125]. It ofsimultaneously the mitochondrial cause functiond intrinsic [119 ]. Thepathway complex-dependent exhibited apoptosis selective and cytotoxicity apoptosis- todep T-24endent cells. pro-death autophagy in A549 cells. The interactions of 48 (Figure 16) with different topologies of DNA imply that it 5.interacted Miscellaneous with DNA Monofunctinoal non-covalently, Pt butII Complexescould degrade once reacted with proteins, forming adducts with different Pt/protein ratios [126]. This unusual mechanism of action may Generally, Pt drugs induce cancer cell death by interfering with DNA synthesis or origin from the peculiar reactivity with biomacromolecules. causing chemical damage to DNA, which is mainly manifested by apoptosis. However, accumulating evidences indicate that Pt drugs may have other molecular targets in addition to DNA, which can induce cell death through non-apoptotic pathways, such as autophagy, necrosis, and even immunogenicity [105,120–123]. Complexes 44–46 (Figure 16) showed a dose-dependent antiproliferative activity in the A2780 cells, with the cytotoxicity order of 44 < 45 < 46, by a combinative apoptotic mechanism involving mitochondrial and autophagic pathways [124]. Complex 47 (Figure 16) not only initiated a series of events associated with mitochondrial dysfunction, but also induced an apparent ER stress through the ROS release and TrxR inhibition [125]. It simultaneously caused intrinsic pathway- dependent apoptosis and apoptosis-dependent pro-death autophagy in A549 cells. The interactions of 48 (Figure 16) with different topologies of DNA imply that it interacted with DNA non-covalently, but could degrade once reacted with proteins, forming adducts with different Pt/protein ratios [126]. This unusual mechanism of action may origin from the peculiar reactivity with biomacromolecules.

Figure 16. Chemical structures of complexes 44‒48.

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Figure 15. Chemical structures of complexes 40‒43.

5. Miscellaneous Monofunctinoal PtII Complexes Generally, Pt drugs induce cancer cell death by interfering with DNA synthesis or causing chemical damage to DNA, which is mainly manifested by apoptosis. However, accumulating evidences indicate that Pt drugs may have other molecular targets in addition to DNA, which can induce cell death through non-apoptotic pathways, such as autophagy, necrosis, and even immunogenicity [105,120–123]. Complexes 44–46 (Figure 16) showed a dose-dependent antiproliferative activity in the A2780 cells, with the cytotoxicity order of 44 < 45 < 46, by a combinative apoptotic mechanism involving mitochondrial and autophagic pathways [124]. Complex 47 (Figure 16) not only initiated a series of events associated with mitochondrial dysfunction, but also induced an apparent ER stress through the ROS release and TrxR inhibition [125]. It simultaneously caused intrinsic pathway-dependent apoptosis and apoptosis-dependent pro-death autophagy in A549 cells. The interactions of 48 (Figure 16) with different topologies of DNA imply that it Pharmaceuticals 2021, 14, 133 interacted with DNA non-covalently, but could degrade once reacted with proteins, form-14 of 23 ing adducts with different Pt/protein ratios [126]. This unusual mechanism of action may origin from the peculiar reactivity with biomacromolecules.

Pharmaceuticals 2021, 14, x FOR PEERFigureFigure REVIEW 16. ChemicalChemical structures structures of of complexes complexes 4444‒48–48. . 15 of 24

Some monofunctional PtII complexes exhibit unique properties due to special structures.Some Complex monofunctional49 (Figure Pt 17II complexes) could weaken exhibit theunique viability properties and invasibilitydue to special of struc- the human seminomatures. Complex cells 49 through (Figure the17) could PI3K/Akt weaken signaling the viability and and mitochondria-mediated invasibility of the human apoptotic pathwaysseminoma [cells127 ]. through It may the serve PI3K/Akt as a potential signaling drug and in mitochondria the treatment-mediated of testicular apoptotic germ cell tumors.pathways Complexes [127]. It may50 −serve53 (Figure as a potential 17) showed drug in different the treatment biological of testicular activities germ owing cell to their differenttumors. Complexe conformations,s 50−53 (Figure among 1 which7) showed50 and different51 with biological a cis configuration activities owing exhibited to their higher anticancerdifferent conformations, activity than among52 and which53 with 50 and a trans51 with configuration a cis configuration towards exhibited cancer higher cells [128]. Concretely,anticancer activity complexes than 5250 andand 5351 withshowed a trans a highconfiguration affinity fortowards the minor cancer groovescells [128]. of DNA, whileConcret52ely,and complexes53 moderately 50 and bind51 showed to the a major high affinity grooves for of the DNA. minor The grooves enhanced of DNA, anticancer activitywhile 52 ofand50 53and moderately51 may bebind attributed to the major to theirgrooves higher of DNA. affinity The enhanced for nDNA anticancer due to the for- mationactivity of 50 aqua and species51 may inbe theattributed cell culture. to their Allhigher these affinity complexes for nDNA significantly due to the for- increased thematio generationn of aqua species of ROS, in the which cell culture. consequently All these depolarized complexes significantly the mitochondrial increased membrane the andgeneration damaged of ROS, the nDNA. which consequently Thus, the cis depolariz-complexesed the can mitochondrial be regarded as membrane mitochondrial and and DNA-targetingdamaged the nDNA. anticancer Thus, the agents. cis-complexes In complex can be54 regarded(Figure as 17 mitochondrial), ferrocenyl and terpyridine DNA- led targeting anticancer agents. In complex 54 (Figure 17), ferrocenyl terpyridine led to a dra- to a dramatic decrease in the dark toxicity [129]. However, it showed a low lying broad matic decrease in the dark toxicity [129]. However, it showed a low lying broad absorption absorption band at 600 nm and excellent ROS-mediated photocytotoxicity in visible light, band at 600 nm and excellent ROS-mediated photocytotoxicity in visible light, with IC50 µ withvalues IC of50 9.5values and 12 of μM 9.5 andin HaCaT 12 M and in HaCaTMCF-7 cell and lines, MCF-7 respectively, cell lines, which respectively, imply that which 54 imply thatcould54 actcould as an act photoinitiator as an photoinitiator in visible light. in visible light.

FigureFigure 17. 17. ChemicalChemical structures structures of ofcomplexes complexes 49‒5449.– 54.

Considering the the timeliness timeliness and and novelty novelty of the of literature, the literature, the ab theove above mentioned mentioned com- com- poundspounds do do not not cover cover all all the the monofunctional monofunctional PtII PtcomplexesII complexes and their and theirresearch research scope. scope.If If readersreaders are are interested interested in in more more details details on onthe theabove above comp complexes,lexes, please please refer to refer the tooriginal the original paperspapers and and the the following following summary summary Table Table 1. 1.

Pharmaceuticals 2021, 14, 133 15 of 23

Table 1. Summary of monofunctional PtII complexes 1−54.

Complex Functional Group Function Tested Cells or Animals Ref. Fluorescent Complexes 1 anthraquinone monitor subcellular localization U2-OS, U2-OS/Pt, A2780, A2780/DDP [40] 2, 3 4-nitrobenzo-2-oxa-1,3-diazole track cellular distribution HeLa [43] 4 4-amino-7-nitro-2,1,3- benzoxadiazole in vitro and vivo fluorescence imaging MCF-7, A549, 293T; zebrafish larva [44] 5 ThT derivative cellular imaging HeLa [45] Photoactive Complexes 6, 7 isomeric tetra-cationic(pyridyl)porphyrins PDT on metastatic melanoma cells WM1366 [56] 8 5,10,15,20-tetra-(4-pyridyl)-21H,23H-porphine photocytotoxicity (50 W LED light, 6 J cm−2, 30 min) colon26, sarcoma180; colon26 tumor-bearing mice [57] photocytotoxicity (6.95 J cm−2, 420 nm, 15 min), 9 5,10,15,20-tetra(4-pyridyl)porphyrin MRC-5, HeLa, A2780, CP70 [51] DNA photocleavage 10 porphyrin containing GaIII center singlet oxygen generator, photocytotoxicity, DNA interaction colon 26, sarcoma 180; colon26 tumor-bearing mice [59] specific cellular uptake, mitochondrial accumulation, 11 SiIV phthalocyanine MDA-MB-231, HEK293T [62] photocytotoxicity (45 min, 660–680 nm, 5.5 ± 2.5 mW cm−2) 12, 13 SiIV phthalocyanine photocytotoxicity, DNA-targeting PDT agents HeLa [63] 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) and its photocytotoxicity (400−700 nm, 14, 15 HaCaT, MCF-7 [64] diiodo derivative 10 J cm−2), cellular imaging photocytotoxicity (532 nm, 16 α-(4-amino)styryl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene MCF-7, SGC-7901, A549, HeLa [66] 3.5 mW cm−2, 5 min) photocytotoxicity, lysosomal escape, increase accessibility to 17 α-(4-amino)styryl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene MCF-7, SGC-7901, A549, HeLa [70] nDNA, decrease intracellular GSH HeLa, HepG2, A549, A549cisR, LO2; HeLa 18–21 triphenylamine core PDT activity [76] xenograft-bearing nude mice Targeted Complexes 22–23 bisphosphonate bone targeting U2-OS, MG-63; male ICR mice [84] 24 bisphosphonate bone targeting, decrease systemic toxicity U2-OS, MG-63, LO2; male ICR mice [85] 25 c(RGDyK) tumor targeting, integrin-targeted PDT SKOV-3, PC-3, A549, MCF-7, MDA-MB-231, U87M [88] 26 cyclic peptide containing RGD sequence (-Arg-Gly-Asp-) target angiogenesis, antiangiogenic and antitumor activity SK-MEL-28, MDA-MB-231, CAPAN-1, HUVEC [89] 4,4’-bipyridine, 1,2-di(pyridin-4-yl)ethane, or target angiogenesis, overcome cisplatin resistance, block tumor MRC-5, A549, A375; B16-F10 melanoma-zebrafish, 27–29 [91] 1,2-di(pyridin-4-yl)ethene neovascularization and metastasis HCT-116-zebrafish target mtDNA, damage mtDNA, regulate mtDNA-encoded 30 naphthalimide MCF-7, A549, Caov-3, HK-2; MCF-7 tumor-bearing mice [102] protein, disturb mitochondrial physiological process IrIII moiety plus imidazo[4,5-f][1,10]phenanthroline target mtDNA, accumulate in mitochondria, induce 31 HepG2, HeLa, A549, A549R [103] derivative mitochondrial dysfunction via mtDNA damage target mtDNA, inhibit glycolysis, affect mitochondrial structure 32–34 triphenylphosphonium A549, HeLa, SMMC, HL-7720; A549 tumor-bearing mice [104] and function, damage mtDNA target mitochondrion, inhibit mitochondrial TrxR, destroy 35 triphenylphosphonium Caov-3, A549, A549R, HK-2 [105] respiratory and glycolytic metabolisms target tyrosine phosphatases, selectively inhibit PTP1B, 36 5-chlorosalicylideneaniline MCF-7, HepG2, A549 [110] antiproliferative activity Pharmaceuticals 2021, 14, 133 16 of 23

Table 1. Cont.

Complex Functional Group Function Tested Cells or Animals Ref. target hexokinase, disrupt mitochondrial bioenergetics, 37–39 lonidamine A549, PC3, Caov-3, MCF-7, MDA-MB-231, MCF-10A [113] damage mtDNA target telomerase, inhibit telomerase, disrupt SKOV-3, NCI-H460, HeLa, HL-7702, BEL-7402; NCI-H460 40, 41 naphthalene imide derivatives [116,117] mitochondrial function tumor-bearing mice target telomerase and p53, cause mitochondrial and DNA SKOV-3/DDP, T-24, HeLa, HL-7702, A549; HeLa 42 jatrorrhizine derivative [118] damage, display antitumor activity and green luminescence tumor-bearing mice target telomerase, inhibit telomerase by interacting with c-myc 43 4-([2,20:60,200-terpyridin]-40-yl)-N,N-diethylaniline BEL-7404, A549, MGC80-3, T-24, HL-7702 [119] quadruplex, disrupt mitochondrial function Miscellaneous Complexes 9-anthryl, 9-phenantryl, and 1-pyrenyl participate in apoptotic mechanism involving mitochondrial and 44–46 MCF-7, PC3, HCT-116, A2780, Fibroblasts [124] 2,6-bis(thiazol-2-yl)pyridines autophagic pathways BEL-7404, SKOV-3, HepG2, HCT-116, HL-7702; A549 47 8-substituted quinoline derivatives induce ER stress, cause apoptosis and pro-death autophagy [125] tumor-bearing mice 48 terpyridine with two piperidine substituents peculiar reactivity with biological macromolecules (proteins) hen egg white lysozyme (HEWL, protein) [126] induce apoptosis via PI3K/Akt signaling and 49 6,7-dichloro-5,8-quinolinedione TCam-2, SEM-1 [127] mitochondria-mediated apoptotic pathways 50–53 mono- and dialkylphenylphosphines conformation-dependent biological activity MCF-7, A549, BEAS-2B, HCT-116 [128] photocytotoxicity in visible light 54 ferrocenyl-terpyridine HaCaT [129] (400–700 nm) Pharmaceuticals 2021, 14, 133 17 of 23

6. Conclusions Platinum-based anticancer agents are the mainstay of chemotherapy regimens. Their drawbacks such as inherent or acquired drug resistance and systemic toxicity have stimu- lated the exploration of new possible drugs. Monofunctional PtII complexes are a potential new type of metallodrugs that break the traditional structure-activity relationships of platinum drugs and exhibit improved therapeutic efficacy. In this review, we introduced the basic conception of monofunctional PtII complexes and summed up some representative properties and potential applications. Fluorescent monofunctional complexes have the potentiality to monitor their distribution and travelling track in vitro and vivo with a high temporal and spatial resolution, which would help in understanding the therapeutic process of the complexes. Photoactive monofunctional complexes combine chemotherapy with photodynamic therapy, which provide a dual mechanism involving light-induced ROS and direct DNA damage to potentiate the action of PDT in hypoxic regions and overcome the drug resistance. Targeted monofunctional complexes could increase the amount of Pt content at the tumor site and avoid the side reactions with normal cells, thereby enhancing the efficacy and reducing the systemic toxicity of the complexes. All these characteristics have gone beyond the properties of existing platinum-based anticancer drugs. Simplicity in the synthesis in comparison with organic drugs is another advantage of monofunctional PtII complexes, or rather, all kinds of Pt complexes. Typically, there + are three synthetic routes to these complexes. (1) For [Pt(NH3)2(Am)Cl] complexes, one chloride ion in cisplatin was first removed by silver nitrate or silver sulfate in dimethylfor- mamide (DMF), and amine (Am) was then added to the solution. The goal product was obtained after the addition of diethyl ether or other organic solvents. (2) For [Pt(3Am)Cl]+ (Am = aromatic N-heterocyclic amine) complexes, a direct reaction between potassium tetrachloroplatinate(II) (K2PtCl4) and Am in dimethyl sulfoxide (DMSO) would give the target product. (3) Alternatively, cis-[Pt(DMSO)2(Cl)2] or bis(benzonitrile) dichloroplat- inum(II) [Pt(PhCN)2Cl2] was mixed with Am in an organic solution (methanol or a mixture of methanol and acetonitrile/DMSO/acetone) to obtain the monofunctional PtII complex. If necessary, Am could be functionalized beforehand. Last but not least, current researches on monofunctional PtII complexes are largely limited to the molecular and cellular levels, or at best to simple animal tests. Pharma- cokinetic and clinical trial data are completely absent, which greatly hinder any objective assessment for the prospective development of these drug candidates. Recently, our studies indicate that some monofunctional PtII complexes do not react with DNA but still display anticancer activity [105,130]. The findings suggest that the known mechanism of action for these complexes is not impeccable, and many unknown facts need to be revealed in the future. In some less focused sides, the identification of molecular target and target-oriented molecular design, as well as the revealing of a new anticancer mechanism would be a meaningful aspect for the research of monofunctional PtII complexes.

Author Contributions: Conceptualization, X.W, and Z.G.; writing—original draft preparation, S.J. and Y.G.; writing—review and editing, X.W.; supervision, X.W.; funding acquisition, X.W. and Z.G. All authors have read and agreed to the published version of the manuscript. Funding: We acknowledge the financial support from the National Natural Science Foundation of China (grants 31570809, 21877059, 21731004, 91953201), the Natural Science Foundation of Jiangsu Province (BK20202004), and the Key Scientific Research Project of Colleges and Universities in He’nan Province (21A150009). Conflicts of Interest: The authors declare no conflict of interest. Pharmaceuticals 2021, 14, 133 18 of 23

Appendix A

Table A1. Designations of cell lines.

Codes Designated Cell Lines A2780; CP70 human ovarian cancer cell A2780/DDP cisplatin-resistant human ovarian cancer cell A375 human melanoma cell A549 human lung carcinoma cell A549cisR; A549R cisplatin-resistant human lung carcinoma cell B16-F10 mouse melanoma cell BEAS-2B human normal bronchial epithelial cell BEL-7402 human hepatoma cell Caov-3 human ovarian cancer cell CAPAN-1 human pancreatic adenocarcinoma cell colon26 murine colon carcinoma cell HaCaT human keratinocyte HCT-116 human colon carcinoma cell HEK293T; 293T human embryonic kidney cell HeLa human cervical carcinoma cell HepG2 human hepatocarcinoma cell HK-2 human renal tubular epithelial cell HL-7702; LO2 human normal liver cell HUVEC human umbilical vein endothelial cell MCF-10A human normal breast epithelial cell MCF-7 human breast adenocarcinoma cell MDA-MB-231 human breast cancer cell MG-63 human osteosarcoma cell MGC80-3 human gastric adenocarcinoma cell MRC-5 human normal lung ﬁbroblast cell NCI-H460 human lung carcinoma cell PC-3; PC3 human prostate cancer cell sarcoma180 mouse sarcoma cell SEM-1 human testicular seminoma cell SGC-7901 human gastric adenocarcinoma cell SK-MEL-28 human melanoma cell SKOV-3 human ovarian cancer cell SKOV-3/DDP cisplatin-resistant human ovarian cancer cell SMMC human hepatocellular carcinoma cell T-24 human bladder cancer cell TCam-2 human testicular seminoma cell U2-OS human osteosarcoma cell U2-OS/Pt cisplatin-resistant human osteosarcoma cell U87M human glioblastoma cell WM1366 human melanoma cell

References 1. Shimada, M.; Itamochi, H.; Kigawa, J. Nedaplatin: A cisplatin derivative in cancer chemotherapy. Cancer Manag. Res. 2013, 5, 67–76. [CrossRef] 2. McKeage, M.J. Lobaplatin: A new antitumour platinum drug. Expert. Opin. Investig. Drugs 2001, 10, 119–128. [CrossRef] 3. Lee, K.H.; Hyun, M.S.; Kim, H.K.; Jin, H.M.; Yang, J.; Song, H.S.; Do, Y.R.; Ryoo, H.M.; Chung, J.S.; Zang, D.Y.; et al. Randomized, multicenter, phase III trial of heptaplatin 1-h infusion and 5-ﬂuorouracil combination chemotherapy comparing with cisplatin and 5-ﬂuorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res. Treat. 2009, 41, 12–18. [CrossRef] 4. Kenny, R.G.; Chuah, S.W.; Crawford, A.; Marmion, C.J. Platinum(IV) prodrugs—A step closer to Ehrlich’s vision? Eur. J. Inorg. Chem. 2017, 2017, 1596–1612. [CrossRef] 5. Johnstone, T.C.; Suntharalingam, K.; Lippard, S.J. The next generation of platinum drugs: Targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem. Rev. 2016, 116, 3436–3486. [CrossRef] 6. Dilrub, S.; Kalayd, G.V. Platinum-based drugs: Past, present and future. Cancer Chemother. Pharm. 2016, 77, 1103–1124. [CrossRef] 7. Wang, X.Y.; Guo, Z.J. Towards the rational design of platinum(II) and gold(III) complexes as antitumour agents. Dalton Trans. 2008, 1521–1532. [CrossRef][PubMed] Pharmaceuticals 2021, 14, 133 19 of 23

8. Argyriou, A.A.; Polychronopoulos, P.; Iconomou, G.; Chroni, E.; Kalofonos, H.P. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat. Rev. 2008, 34, 368–377. [CrossRef][PubMed] 9. McWhinney, S.R.; Goldberg, R.M.; McLeod, H.L. Platinum neurotoxicity pharmacogenetics. Mol. Cancer Ther. 2009, 8, 10–16. [CrossRef] 10. Min, Y.Z.; Mao, C.Q.; Chen, S.M.; Ma, G.L.; Wang, J.; Liu, Y.Z. Combating the drug resistance of cisplatin using a platinum prodrug based delivery system. Angew. Chem. Int. Ed. 2012, 51, 6742–6747. [CrossRef] 11. Wang, D.; Lippard, S.J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov. 2005, 4, 307–320. [CrossRef] 12. Brabec, V.; Hrabina, O.; Kasparkova, J. Cytotoxic platinum coordination compounds. DNA binding agents. Coord. Chem. Rev. 2017, 351, 2–31. [CrossRef] 13. Usanova, S.; Piée-Staffa, A.; Sied, U.; Thomale, J.; Schneider, A.; Kaina, B.; Köberle, B. Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol. Cancer 2010, 9, 248. [CrossRef][PubMed] 14. Sakai, W.; Swisher, E.M.; Karlan, B.Y.; Agarwal, M.K.; Higgins, J.; Friedman, C.; Villegas, E.; Jacquemont, C.; Farrugia, D.J.; Couch, F.J.; et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008, 451, 1116–1120. [CrossRef][PubMed] 15. Johnstone, T.C.; Park, G.Y.; Lippard, S.J. Understanding and improving platinum anticancer drugs—Phenanthriplatin. Anticancer Res. 2014, 34, 471–476. [PubMed] 16. Guo, W.J.; Zhang, Y.M.; Zhang, L.; Huang, B.; Tao, F.F.; Chen, W.; Guo, Z.J.; Xu, Q.; Sun, Y. Novel monofunctional platinum(II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells, distinct from cisplatin. Autophagy 2013, 9, 996–1008. [CrossRef] 17. Riddell, I.A.; Johnstone, T.C.; Park, G.Y.; Lippard, S.J. Nucleotide binding preference of the monofunctional platinum anticancer- agent phenanthriplatin. Chem. Eur. J. 2016, 22, 7574–7581. [CrossRef] 18. Malina, J.; Farrell, N.P.; Brabec, V. DNA condensing effects and sequence selectivity of dna binding of antitumor noncovalent polynuclear platinum complexes. Inorg. Chem. 2014, 53, 1662–1671. [CrossRef] 19. Johnstone, T.C.; Lippard, S.J. The chiral potential of phenanthriplatin and its influence on guanine binding. J. Am. Chem. Soc. 2014, 136, 2126–2134. [CrossRef] 20. Johnstone, T.C.; Alexander, S.M.; Lin, W.; Lippard, S.J. Effects of monofunctional platinum agents on bacterial growth: A retrospective study. J. Am. Chem. Soc. 2014, 136, 116–118. [CrossRef] 21. Lovejoy, K.S.; Serova, M.; Bieche, I.; Emami, S.; D’Incalci, M.; Broggini, M.; Erba, E.; Gespach, C.; Cvitkovic, E.; Faivre, S.; et al. Spectrum of cellular responses to pyriplatin, a monofunctional cationic antineoplastic platinum(II) compound, in human cancer cells. Mol. Cancer Ther. 2011, 10, 1709–1719. [CrossRef] 22. Zhou, W.; Almeqdadi, M.; Xifaras, M.E.; Riddell, I.A.; Yilmaz, Ö.H.; Lippard, S.J. The effect of geometric isomerism on the anticancer activity of the monofunctional platinum complex trans-[Pt(NH3)2(phenanthridine)Cl]NO3. Chem. Commun. 2018, 54, 2788–2791. [CrossRef] 23. Johnstone, T.C.; Wilson, J.J.; Lippard, S.J. Monofunctional and higher-valent platinum anticancer agents. Inorg. Chem. 2013, 52, 12234–12249. [CrossRef][PubMed] 24. Macquet, J.P.; Butour, J.L. Platinum-amine compounds: Importance of the labile and inert ligands for their pharmacological activities toward L1210 leukemia cells. J. Natl. Cancer Inst. 1983, 70, 899–905. [PubMed] 25. Cleare, M.J.; Hoeschele, J.D. Antitumor activity of group VIII transition metal complexes. I. Platinum(II) complexes. Bioinorg. Chem. 1973, 2, 187–210. [CrossRef] 26. Sundquist, W.I.; Bancroft, D.P.; Lippard, S.J. Synthesis, characterization, and biological activity of cis-diammineplatinum(II) complexes of the DNA intercalators 9-aminoacridine and chloroquine. J. Am. Chem. Soc. 1990, 112, 1590–1596. [CrossRef] 27. Hollis, L.S.; Sundquist, W.I.; Burstyn, J.N.; Heiger-Bernays, W.J.; Bellon, S.F.; Ahmed, K.J.; Amundsen, A.R.; Stern, E.W.; Lippard, S.J. Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents. Cancer Res. 1991, 51, 1866–1875. 28. Zhang, S.; Lovejoy, K.S.; Shima, J.E.; Lagpacan, L.L.; Shu, Y.; Lapuk, A.; Chen, Y.; Komori, T.; Gray, J.W.; Chen, X.; et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006, 66, 8847–8857. [CrossRef] 29. Lovejoy, K.S.; Todd, R.C.; Zhang, S.; McCormick, M.S.; D’Aquino, J.A.; Reardon, J.T.; Sancar, A.; Giacomini, K.M.; Lippard, S.J. cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects. Proc. Natl. Acad. Sci. USA 2008, 105, 8902–8907. [CrossRef] 30. Wang, D.; Zhu, G.Y.; Huang, X.H.; Lippard, S.J. X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct. Proc. Natl. Acad. Sci. USA 2010, 107, 9584–9589. [CrossRef] 31. Park, G.Y.; Wilson, J.J.; Song, Y.; Lippard, S.J. Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile. Proc. Natl. Acad. Sci. USA 2012, 109, 11987–11992. [CrossRef] [PubMed] 32. Casini, A.; Reedijk, J. Interactions of anticancer Pt compounds with proteins: An overlooked topic in medicinal inorganic chemistry. Chem. Sci. 2012, 3, 3135–3144. [CrossRef] 33. Kellinger, M.W.; Park, G.Y.; Chong, J.; Lippard, S.J.; Wang, D. Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis. J. Am. Chem. Soc. 2013, 135, 13054–13061. [CrossRef][PubMed] 34. Almaqwashi, A.A.; Zhou, W.; Naufer, M.N.; Riddell, I.A.; Yilmaz, Ö.H.; Lippard, S.J.; Williams, M.C. DNA intercalation facilitates efficient DNA-targeted covalent binding of phenanthriplatin. J. Am. Chem. Soc. 2019, 141, 1537–1545. [CrossRef][PubMed] Pharmaceuticals 2021, 14, 133 20 of 23

35. Gregory, M.T.; Park, G.Y.; Johnstone, T.C.; Lee, Y.S.; Yang, W.; Lippard, S.J. Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage. Proc. Natl. Acad. Sci. USA 2014, 111, 9133–9138. [CrossRef][PubMed] 36. Baruah, H.; Rector, C.L.; Monnier, S.M.; Bierbach, U. Mechanism of action of non-cisplatin type DNA-targeted platinum anticancer agents: DNA interactions of novel acridinylthioureas and their platinum conjugates. Biochem. Pharm. 2002, 64, 191–200. [CrossRef] 37. Guddneppanavar, R.; Saluta, G.; Kucera, G.L.; Bierbach, U. Synthesis, biological activity, and DNA-damage profile of platinum threading intercalator conjugates designed to target adenine. J. Med. Chem. 2006, 49, 3204–3214. [CrossRef][PubMed] 38. Guddneppanavar, R.; Choudhury, J.R.; Kheradi, A.R.; Steen, B.D.; Saluta, G.; Kucera, G.L.; Day, C.S.; Bierbach, U. Effect of the diamine nonleaving group in platinum-acridinylthiourea conjugates on DNA damage and cytotoxicity. J. Med. Chem. 2007, 50, 2259–2263. [CrossRef] 39. Smyre, C.L.; Saluta, G.; Kute, T.E.; Kucera, G.L.; Bierbach, U. Inhibition of DNA synthesis by a platinum−acridine hybrid agent leads to potent cell kill in nonsmall cell lung cancer. ACS Med. Chem. Lett. 2011, 2, 870–874. [CrossRef] 40. Kalayda, G.V.; Jansen, B.A.J.; Wielaard, P.; Tanke, H.J.; Reedijk, J. Dinuclear platinum anticancer complexes with fluorescent N,N’-bis(aminoalkyl)-1,4-diaminoanthraquinones: Cellular processing in two cisplatin-resistant cell lines reflects the differences in their resistance profiles. J. Biol. Inorg. Chem. 2005, 10, 305–315. [CrossRef] 41. Kalayda, G.V.; Jansen, B.A.J.; Molenaar, C.; Wielaard, P.; Tanke, H.J.; Reedijk, J. Dinuclear platinum complexes with N,N’- bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells: New insights into the mechanism of resistance. J. Biol. Inorg. Chem. 2004, 9, 414–422. [CrossRef] 42. Jansen, B.A.J.; Wielaard, P.; Kalayda, G.V.; Ferrari, M.; Molenaar, C.; Tanke, H.J.; Brouwer, J.; Reedijk, J. Dinuclear platinum complexes with N,N’-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part I. Synthesis, cytotoxicity, and cellular studies in gA2780 human ovarian carcinoma cells. J. Biol. Inorg. Chem. 2004, 9, 403–413. [CrossRef] 43. Wu, S.D.; Wang, X.Y.; Zhu, C.C.; Song, Y.J.; Wang, J.; Li, Y.Z.; Guo, Z.J. Monofunctional platinum complexes containing a 4-nitrobenzo-2-oxa-1,3-diazole fluorophore: Distribution in tumour cells. Dalton Trans. 2011, 40, 10376–10382. [CrossRef] [PubMed] 44. Wu, S.D.; Zhu, C.C.; Zhang, C.L.; Yu, Z.; He, W.J.; He, Y.F.; Li, Y.Z.; Wang, J.; Guo, Z.J. In vitro and in vivo fluorescent imaging of a monofunctional chelated platinum complex excitable using visible light. Inorg. Chem. 2011, 50, 11847–11849. [CrossRef] 45. Chen, Z.F.; Zhang, S.P.; Shen, L.; Zhu, Z.Z.; Zhang, J. Fluorescence imaging of a new monofunctional platinum(II) complex containing a thioflavin-T (ThT)-based fluorophore. New J. Chem. 2015, 39, 1592–1596. [CrossRef] 46. Zhang, C.; Guan, R.L.; Liao, X.X.; Ouyang, C.; Rees, T.W.; Liu, J.P.; Chen, Y.; Ji, L.N.; Chao, H. A mitochondria-targeting dinuclear Ir-Ru complex as a synergistic photoactivated chemotherapy and photodynamic therapy agent against cisplatin-resistant tumour cells. Chem. Commun. 2019, 55, 12547–12550. [CrossRef] 47. Bonnet, S. Why develop photoactivated chemotherapy? Dalton Trans. 2018, 47, 10330–10343. [CrossRef][PubMed] 48. Dabids, L.M.; Kleemann, B. Combating melanoma: The use of photodynamic therapy as a novel, adjuvant therapeutic tool. Cancer Treat Rev. 2011, 37, 465–475. 49. Zhou, Z.J.; Song, J.B.; Nie, L.M.; Chen, X.Y. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem. Soc. Rev. 2016, 45, 6597–6626. [CrossRef] 50. Ethirajan, M.; Chen, Y.H.; Joshi, P.; Pandey, R.K. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem. Soc. Rev. 2011, 40, 340–362. [CrossRef][PubMed] 51. Naik, A.; Rubbiani, R.; Gasser, G.; Spingler, B. Visible-light-induced annihilation of tumor cells with platinum-porphyrin conjugates. Angew. Chem. Int. Ed. 2014, 53, 6938–6941. [CrossRef][PubMed] 52. Yu, G.C.; Yu, S.; Saha, M.L.; Zhou, J.; Cook, T.R.; Yung, B.C.; Chen, J.; Mao, Z.W.; Zhang, F.W.; Zhou, Z.J.; et al. A discrete organoplatinum(II) metallacage as a multimodality theranostic platform for cancer photochemotherapy. Nat. Commun. 2018, 9, 4335. [CrossRef] 53. Santoro, A.M.; Lo Giudice, M.C.; D’Urso, A.; Lauceri, R.; Purrello, R.; Milardi, D. Cationic porphyrins are reversible proteasome inhibitors. J. Am. Chem. Soc. 2012, 134, 10451–10457. [CrossRef] 54. Bacellar, I.O.; Tsubone, T.M.; Pavani, C.; Baptista, M.S. Photodynamic efficiency: From molecular photochemistry to cell death. Int. J. Mol. Sci. 2015, 16, 20523–20559. [CrossRef][PubMed] 55. Tasso, T.T.; Tsubone, T.M.; Baptista, M.S.; Mattiazzi, L.M.; Acunha, T.V.; Iglesias, B.A. Isomeric effect on the properties of tetraplatinated porphyrins showing optimized phototoxicity for photodynamic therapy. Dalton Trans. 2017, 46, 11037–11045. [CrossRef] 56. Couto, G.K.; Pacheco, B.S.; Borba, V.M.; Junior, J.C.R.; Oliveira, T.L.; Segatto, N.V.; Seixas, F.K.; Acunha, T.V.; Iglesias, B.A.; Collares, T. Tetra-cationic platinum(II) porphyrins like a candidate photosensitizers to bind, selective and drug delivery for metastatic melanoma. J. Photoch. Photobio. B. 2020, 202, 111725. [CrossRef] 57. Hu, X.J.; Ogawa, K.; Li, S.; Kiwada, T.; Odani, A. A platinum functional porphyrin conjugate: An excellent cancer killer for photodynamic therapy. Bull. Chem. Soc. Jpn. 2019, 92, 790–796. [CrossRef] 58. Xu, X.L.; Lin, F.W.; Du, Y.; Zhang, X.; Wu, J.; Xu, Z.K. Graphene oxide nanofiltration membranes stabilized by cationic porphyrin for high salt rejection. Acs Appl. Mater. Interfaces 2016, 8, 12588–12593. [CrossRef][PubMed] 59. Hu, X.J.; Ogawa, K.; Kiwada, T.; Odani, A. Water-soluble metalloporphyrinates with excellent photo-induced anticancer activity resulting from high tumor accumulation. J. Inorg. Biochem. 2017, 170, 1–7. [CrossRef] Pharmaceuticals 2021, 14, 133 21 of 23

60. Li, X.; Zheng, B.D.; Peng, X.H.; Li, S.Z.; Ying, J.W.; Zhao, Y.; Huang, J.D.; Yoon, J. Phthalocyanines as medicinal photosensitizers: Developments in the last five years. Coord. Chem. Rev. 2017, 379, 147–160. [CrossRef] 61. Wonga, R.C.H.; Lo, P.C.; Ng, D.K.P. Stimuli responsive phthalocyanine-based fluorescent probes and photosensitizers. Coord. Chem. Rev. 2017, 379, 30–46. [CrossRef] 62. Mitra, K.; Samsó, M.; Lyonsb, C.E.; Hartman, M.C.T. Hyaluronic acid grafted nanoparticles of a platinum(II)–silicon(IV) phthalocyanine conjugate for tumor and mitochondria-targeted photodynamic therapy in red light. J. Mater. Chem. B 2018, 6, 7373–7377. [CrossRef][PubMed] 63. Mao, J.F.; Zhang, Y.M.; Zhu, J.H.; Zhang, C.L.; Guo, Z.J. Molecular combo of photodynamic therapeutic agent silicon(IV) phthalocyanine and anticancer drug cisplatin. Chem. Commun. 2009, 908–910. [CrossRef] 64. Raza, M.K.; Gautam, S.; Garai, A.; Mitra, K.; Kondaiah, P.; Chakravarty, A.R. Monofunctional BODIPY-appended imidazoplatin for cellular imaging and mitochondria-targeted photocytotoxicity. Inorg. Chem. 2017, 56, 11019–11029. [CrossRef][PubMed] 65. Wang, B.; Yuan, H.X.; Liu, Z.; Nie, C.Y.; Liu, L.B.; Lv, F.T.; Wang, Y.L.; Wang, S. Cationic oligo(p-phenylene vinylene) materials for combating drug resistance of cancer cells by light manipulation. Adv. Mater. 2014, 26, 5986–5990. [CrossRef][PubMed] 66. Xue, X.L.; Zhu, C.C.; Chen, H.C.; Bai, Y.; Shi, X.C.; Jiao, Y.; Chen, Z.Y.; Miao, Y.P.; He, W.J.; Guo, Z.J. A new approach to sensitize antitumor monofunctional platinum(II) complexes via short time photo-irradiation. Inorg. Chem. 2017, 56, 3754–3762. [CrossRef] 67. Settembre, C.; Fraldi, A.; Medina, D.L.; Ballabio, A. Signals from the lysosome: A control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 2013, 14, 283–296. [CrossRef] 68. Bonam, S.R.; Wang, F.J.; Muller, S. Lysosomes as a therapeutic target. Nat. Rev. Drug Discov. 2019, 18, 923–948. [CrossRef] [PubMed] 69. Klein, A.V.; Hambley, T.W. Platinum drug distribution in cancer cells and tumors. Chem. Rev. 2009, 109, 4911–4920. [CrossRef] 70. Xue, X.L.; Qian, C.G.; Fang, H.B.; Liu, H.K.; Yuan, H.; Guo, Z.J.; Bai, Y.; He, W.J. Photoactivated lysosomal escape of a monofunctional PtII complex Pt-BDPA for nucleus access. Angew. Chem. Int. Ed. 2019, 58, 12661–12666. [CrossRef][PubMed] 71. Liu, W.T.; Zhong, Y.F.; Liu, L.Y.; Shen, C.T.; Zeng, W.J.; Wang, F.Y.; Yang, D.Z.; Mao, Z.W. Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding. Nat. Commun. 2018, 9, 3496. [CrossRef] [PubMed] 72. Zheng, X.H.; Mu, G.; Zhong, Y.F.; Zhang, T.P.; Cao, Q.; Ji, L.N.; Zhao, Y.; Mao, Z.W. Trigeminal star-like platinum complexes induce cancer cell senescence through quadruplex-mediated telomere dysfunction. Chem. Commun. 2016, 52, 14101–14104. [CrossRef][PubMed] 73. Zhong, Y.F.; Zhang, H.; Liu, W.T.; Zheng, X.H.; Zhou, Y.W.; Cao, Q.; Shen, Y.; Zhao, Y.; Qin, P.Z.; Ji, L.N.; et al. A platinum(II)-based photosensitive tripod as an effective photodynamic anticancer agent through DNA damage. Chem. Eur. J. 2017, 23, 16442–16446. [CrossRef] 74. Cao, Q.; Li, Y.; Freisinger, E.; Qin, P.Z.; Sigel, R.K.O.; Mao, Z.W. G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs. Inorg. Chem. Front. 2017, 4, 10–32. [CrossRef] 75. Dumat, B.; Bordeau, G.; Faurel-Paul, E.; Mahuteau-Betzer, F.; Saettel, N.; Metge, G.; Fiorini-Debuisschert, C.; Charra, F.; Teulade- Fichou, M.P. DNA switches on the two-photon efficiency of an ultrabright triphenylamine fluorescent probe specific of AT regions. J. Am. Chem. Soc. 2013, 135, 12697–12706. [CrossRef][PubMed] 76. Zhong, Y.F.; Zhang, H.; Mu, G.; Liu, W.T.; Cao, Q.; Tan, C.P.; Ji, L.N.; Mao, Z.W. Nucleus-localized platinum(II)–triphenylamine complexes as potent photodynamic anticancer agents. Inorg. Chem. Front. 2019, 6, 2817–2823. [CrossRef] 77. Wang, X.Y.; Guo, Z.J. Targeting and delivery of platinum-based anticancer drugs. Chem. Soc. Rev. 2013, 42, 202–224. [CrossRef] 78. Basu, U.; Banik, B.; Wen, R.; Pathak, R.K.; Dhar, S. The Platin-X series: Activation, targeting, and delivery. Dalton Trans. 2016, 45, 12992–13004. [CrossRef][PubMed] 79. Kansara, M.; Teng, M.T.; Smyth, M.J.; Thomas, D.M. Translational biology of osteosarcoma. Nat. Rev. Cancer 2014, 14, 722–735. [CrossRef] 80. Alpaslan, E.; Yazici, H.; Golshan, N.H.; Ziemer, K.S.; Webster, T.J. pH-dependent activity of dextran-coated cerium oxide nanoparticles on prohibiting osteosarcoma cell proliferation. ACS Biomater. Sci. Eng. 2015, 1, 1096–1103. [CrossRef] 81. Reed, D.E.; Shokat, K.M. Targeting osteosarcoma. Proc. Natl. Acad. Sci. USA 2014, 111, 18100–18101. [CrossRef][PubMed] 82. Whelan, J.S.; Davis, L.E. Osteosarcoma, chondrosarcoma, and chordoma. J. Clin. Oncol. 2018, 36, 188–193. [CrossRef][PubMed] 83. Makris, G.; Tseligka, E.D.; Pirmettis, I.; Papadopoulos, M.S.; Vizirianakis, I.S.; Papagiannopoulou, D. Development and pharmacological evaluation of new bone-targeted 99mTc-radiolabeled bisphosphonates. Mol. Pharm. 2016, 13, 2301–2317. [CrossRef] 84. Zhang, Z.Q.; Wang, X.Y.; Luo, C.; Zhu, C.C.; Wang, K.; Zhang, C.L.; Guo, Z.J. Dinuclear platinum(II) complexes with bone- targeting groups as potential anti-osteosarcoma agents. Chem. Asian J. 2017, 12, 1659–1667. [CrossRef][PubMed] 85. Zhang, Z.Q.; Zhu, Z.Z.; Luo, C.; Zhu, C.C.; Zhang, S.R.; Zhang, C.L.; Guo, Z.J.; Wang, X.Y. A potential bone-targeting hypotoxic platinum(II) complex with an unusual cytostatic mechanism toward osteosarcoma cells. Inorg. Chem. 2018, 57, 3315–3322. [CrossRef] 86. Kenny, R.G.; Marmion, C.J. Toward Multi-targeted platinum and ruthenium drugs-a new paradigm in cancer drug treatment regimens? Chem. Rev. 2019, 119, 1058–1137. [CrossRef][PubMed] 87. Hamidi, H.; Ivaska, J. Every step of the way: Integrins in cancer progression and metastasis. Nat. Rev. Cancer 2018, 18, 533–548. [CrossRef] Pharmaceuticals 2021, 14, 133 22 of 23

88. Chatzisideri, T.; Thysiadis, S.; Katsamakas, S.; Dalezis, P.; Sigala, I.; Lazarides, T.; Nikolakaki, E.; Trafalis, D.; Gederaas, O.A.; Lindgren, M.; et al. Synthesis and biological evaluation of a platinum(II)-c(RGDyK) conjugate for integrin-targeted photodynamic therapy. Eur. J. Med. Chem. 2017, 141, 221–231. [CrossRef] 89. Zamora, A.; Gandioso, A.; Massaguer, A.; Buenestado, S.; Calvis, C.; Hernández, J.L.; Mitjans, F.; Rodríguez, V.; Ruiz, J.; Marchán, V. Toward angiogenesis inhibitors based on the conjugation of organometallic platinum(II) complexes to RGD peptides. ChemMedChem 2018, 13, 1755–1762. [CrossRef] 90. Wu, T.; Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017, 387, 61–68. [CrossRef] 91. Franich, A.A.; Živković,M.D.; Ilić-Tomić,T.; Ðordević,I.S.;¯ Nikodinović-Runić, J.; Pavić,A.; Janjić,G.V.; Rajković,S. New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities. J. Biol. Inorg. Chem. 2020, 25, 395–409. [CrossRef] 92. Martinez-Outschoorn, U.E.; Peiris-Pages, M.; Pestell, R.G.; Sotgia, F.; Lisanti, M.P. Cancer metabolism: A therapeutic perspective. Nat. Rev. Clin. Oncol. 2017, 14, 11–31. [CrossRef] 93. Yang, Y.H.; Karakhanova, S.; Hartwig, W.; D’haese, J.G.; Philippov, P.P.; Werner, J.; Bazhin, A.V. Mitochondria and mitochondrial ros in cancer: Novel targets for anticancer therapy. J. Cell. Physiol. 2016, 231, 2570–2581. [CrossRef][PubMed] 94. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033. [CrossRef] 95. Wallace, D.C. Mitochondria and cancer. Nat. Rev. Cancer. 2012, 12, 685–698. [CrossRef] 96. Marrachea, S.; Dhar, S. The energy blocker inside the power house: Mitochondria targeted delivery of 3-bromopyruvate. Chem. Sci. 2015, 6, 1832–1845. [CrossRef] 97. Taylor, R.W.; Turnbull, D.M. Mitochondrial DNA mutations in human disease. Nat. Rev. Genet. 2005, 6, 389–402. [CrossRef] [PubMed] 98. Bouwman, P.; Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat. Rev. Cancer 2012, 12, 587–598. [CrossRef][PubMed] 99. Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer 2013, 13, 714–726. [CrossRef] 100. Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov. 2010, 9, 447–464. [CrossRef] 101. Lomeli, N.; Di, K.J.; Czerniawski, J.; Guzowski, J.F.; Bota, D.A. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radic. Biol. Med. 2017, 102, 274–286. [CrossRef] 102. Guo, Y.; He, Y.F.; Wu, S.D.; Zhang, S.R.; Song, D.F.; Zhu, Z.Z.; Guo, Z.J.; Wang, X.Y. Enhancing cytotoxicity of a monofunctional platinum complex via a dual-DNA-damage approach. Inorg. Chem. 2019, 58, 13150–13160. [CrossRef] 103. Zhang, C.; Guan, R.L.; Liao, X.X.; Ouyang, C.; Liu, J.P.; Ji, L.N.; Chao, H. Mitochondrial DNA targeting and impairment by a dinuclear Ir–Pt complex that overcomes cisplatin resistance. Inorg. Chem. Front. 2020, 7, 1864–1871. [CrossRef] 104. Zhu, Z.Z.; Wang, Z.H.; Zhang, C.L.; Wang, Y.J.; Zhang, H.M.; Gan, Z.J.; Guo, Z.J.; Wang, X.Y. Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism. Chem. Sci. 2019, 10, 3089–3095. [CrossRef] 105. Wang, K.; Zhu, C.C.; He, Y.F.; Zhang, Z.Q.; Zhou, W.; Muhammad, N.; Guo, Y.; Wang, X.Y.; Guo, Z.J. Restraining cancer cells by dual metabolic inhibition with a mitochondrion-targeted platinum(II) complex. Angew. Chem. Int. Ed. 2019, 58, 4638–4643. [CrossRef][PubMed] 106. Imming, P.; Sinning, C.; Meyer, A. Drugs, Their targets and the nature and number of drug targets. Nat. Rev. Drug Discov. 2006, 5, 821–834. [CrossRef][PubMed] 107. Ramsay, R.; Tipton, K. Assessment of enzyme inhibition: A review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs. Molecules 2017, 22, 1192. [CrossRef][PubMed] 108. Tonks, N.K. Protein tyrosine phosphatases: From genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 2006, 7, 833–846. [CrossRef] 109. Lu, L.P.; Zhu, M.L. Protein tyrosine phosphatase inhibition by metals and metal complexes. Antioxid. Redox Sign. 2014, 20, 2210–2224. [CrossRef] 110. Yuan, C.X.; Wang, W.R.; Wang, J.W.; Li, X.H.; Wu, Y.B.; Li, S.D.; Lu, L.P.; Zhu, M.L.; Xing, S.; Fu, X.Q. Potent and selective PTP1B inhibition by a platinum(II) complex: Possible implications for a new antitumor strategy. Chem. Commun. 2020, 56, 102–105. [CrossRef] 111. Zhang, D.W.; Yip, Y.M.; Li, L.B. In silico construction of HK2-VDAC1 complex and investigating the HK2 binding-induced molecular gating mechanism of VDAC1. Mitochondrion 2016, 30, 222–228. [CrossRef] 112. Li, S.N.; Li, J.J.; Dai, W.Q.; Zhang, Q.H.; Feng, J.; Wu, L.W.; Liu, T.; Yu, Q.; Xu, S.Z.; Wang, W.W.; et al. Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death. Br. J. Cancer. 2017, 117, 1518–1528. [CrossRef] 113. Muhammad, N.; Tan, C.P.; Muhammad, K.; Wang, J.; Sadia, N.; Pan, Z.Y.; Ji, L.N.; Mao, Z.W. Mitochondria-targeting monofunctional platinum(II)–lonidamine conjugates for cancer cell de-energization. Inorg. Chem. Front. 2020, 7, 4010–4019. [CrossRef] 114. Waghorn, P.A.; Jackson, M.R.; Gouverneur, V.; Vallis, K.A. Targeting telomerase with radiolabeled inhibitors. Eur. J. Med. Chem. 2017, 125, 117–129. [CrossRef] Pharmaceuticals 2021, 14, 133 23 of 23

115. Paul, A.; Maji, B.; Misra, S.K.; Jain, A.K.; Muniyappa, K.; Bhattacharya, S. Stabilization and structural alteration of the G- quadruplex DNA made from the human telomeric repeat mediated by Troger’s base based novel benzimidazole derivatives. J. Med. Chem. 2012, 55, 7460–7471. [CrossRef][PubMed] 116. Huang, G.B.; Chen, S.; Qin, Q.P.; Luo, J.R.; Tan, M.X.; Wang, Z.F.; Zou, B.Q.; Liang, H. Preparation of platinum(II) complexes with naphthalene imide derivatives and exploration of their in vitro cytotoxic activities. Inorg. Chem. Commun. 2019, 104, 124–128. [CrossRef] 117. Huang, G.B.; Chen, S.; Qin, Q.P.; Luo, J.R.; Tan, M.X.; Wang, Z.F.; Zou, B.Q.; Liang, H. In vitro and in vivo activity of novel platinum(II) complexes with naphthalene imide derivatives inhibiting human non-small cell lung cancer cells. New J. Chem. 2019, 43, 8146–8152. [CrossRef] 118. Qin, Q.P.; Zou, B.Q.; Wang, Z.F.; Huang, X.L.; Zhang, Y.; Tan, M.X.; Wang, S.L.; Liang, H. High in vitro and in vivo antitumor activities of luminescent platinum(II) complexes with jatrorrhizine derivatives. Eur. J. Med. Chem. 2019, 183, 111727. [CrossRef] 119. Zou, H.H.; Wang, L.; Long, Z.X.; Qin, Q.P.; Song, Z.K.; Xie, T.; Zhang, S.H.; Liu, Y.C.; Lin, B.; Chen, Z.F. Preparation of 4-([2,20:60,200- terpyridin]-40-yl)-N,N-diethylaniline NiII and PtII complexes and exploration of their in vitro cytotoxic activities. Eur. J. Med. Chem. 2016, 108, 1–12. [CrossRef] 120. Sabbatini, M.; Zanellato, I.; Ravera, M.; Gabano, E.; Perin, E.; Rangone, B.; Osella, D. Pt(IV) bifunctional prodrug containing 2-(2-propynyl)octanoato axial ligand: Induction of immunogenic cell death on colon cancer. J. Med. Chem. 2019, 62, 3395–3406. [CrossRef] 121. Wong, D.Y.Q.; Ong, W.W.F.; Ang, W.H. Induction of immunogenic cell death by chemotherapeutic platinum complexes. Angew. Chem. Int. Ed. 2015, 54, 6483–6487. [CrossRef] 122. Huang, K.B.; Wang, F.Y.; Feng, H.W.; Luo, H.J.; Long, Y.; Zou, T.T.; Chan, A.S.C.; Liu, R.; Zou, H.H.; Chen, Z.F.; et al. An aminophosphonate ester ligand-containing platinum(II) complex induces potent immunogenic cell death in vitro and elicits effective anti-tumor immune responses in vivo. Chem. Commun. 2019, 55, 13066–13069. [CrossRef] 123. Al-Khayal, K.; Vaali-Mohammed, M.A.; Elwatidy, M.; Bin Traiki, T.; Al-Obeed, O.; Azam, M.; Khan, Z.; Abdulla, M.; Ahmad, R. A novel coordination complex of platinum (PT) induces cell death in colorectal cancer by altering redox balance and modulating MAPK pathway. Bmc Cancer 2020, 20, 685. [CrossRef][PubMed] 124. Choroba, K.; Machura, B.; Raposo, L.R.; Małecki, J.G.; Kula, S.; Paj ˛ak,M.; Erfurt, K.; Maro´n,A.M.; Fernandes, A.R. Platinum(II) complexes showing high cytotoxicity toward A2780 ovarian carcinoma cells. Dalton Trans. 2019, 48, 13081–13093. [CrossRef] 125. Wang, F.Y.; Tang, X.M.; Wang, X.; Huang, K.B.; Feng, H.W.; Chen, Z.F.; Liu, Y.N.; Liang, H. Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells. Eur. J. Med. Chem. 2018, 155, 639–650. [CrossRef][PubMed] 126. Ferraro, G.; Marzo, T.; Infrasca, T.; Cilibrizzi, A.; Vilar, R.; Messori, L.; Merlino, A. A case of extensive protein platination: The reaction of lysozyme with a Pt(II)–terpyridine complex. Dalton Trans. 2018, 47, 8716–8723. [CrossRef] 127. Li, Z.; Zhou, J.; Gan, Y.; Yin, Y.H.; Zhang, W.C.; Yang, J.F.; Tang, Y.X.; Dai, Y.B. Synthesis of a novel platinum(II) complex with 6,7-dichloro-5,8-quinolinedione and the study of its antitumor mechanism in testicular seminoma. J. Inorg. Biochem. 2019, 197, 110701. [CrossRef][PubMed] 128. Icsel, C.; Yilmaz, V.T.; Cevatemre, B.; Aygun, M.; Ulukaya, E. Structures and anticancer activity of chlorido platinum(II) saccharinate complexes with mono- and dialkylphenylphosphines. J. Inorg. Biochem. 2019, 195, 39–50. [CrossRef] 129. Mitra, K.; Basu, U.; Khan, I.; Maity, B.; Kondaiah, P.; Chakravarty, A.R. Remarkable anticancer activity of ferrocenyl-terpyridine platinum(II) complexes in visible light with low dark toxicity. Dalton Trans. 2014, 43, 751–763. [CrossRef] 130. Zhang, J.Y.; Wang, X.Y.; Tu, C.; Lin, J.; Ding, J.; Lin, L.P.; Wang, Z.M.; He, C.; Yan, C.H.; You, X.Z.; et al. Monofunctional platinum complexes showing potent cytotoxicity against human liver carcinoma cell line BEL-7402. J. Med. Chem. 2003, 46, 3502–3507. [CrossRef]