Classical structure-activity relationships for square-planar Pt(II) anticancer complexes were based on the activity of cis-[PtCl2(NH3)2] (cisplatin) and inactivity of the trans isomer. Many other families of cis-diamine complexes and analogous octahedral Pt(IV) prodrugs are active. Here, we report the chemical and biological activities of isomeric photoactivatable cis,trans,cis- and all-trans-[Pt(N3)2(OH)2(MNZ)2] complexes (MNZ = metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole). While both are relatively nontoxic in the ground state, only the all-trans isomer is cytotoxic toward bladder cancer cells on excitation with visible light and under hypoxia. Studies of DNA interstrand cross-links and photocytotoxicity toward wild-type and nucleotide-excision-repair deficient cells suggest that, unlike cisplatin, DNA is not the major target site of these isomers. Differences in photoactivation pathways were also explored using time-dependent DFT calculations. The key differences between the isomers on irradiation are the more rapid photoactivation of the all-trans complex, generation of azidyl radicals, retention of its metronidazole ligands, higher accumulation in cancer cells, binding to DNA, RNA, and proteins, and induction of apoptosis and mitochondrial membrane damages. These findings provide a basis for the design of future photochemotherapeutic platinum anticancer prodrugs.

Department of Biophysics Faculty of Science Palacky University CZ 77900 Olomouc Czech Republic

Department of Chemistry and Chemical Technologies University of Calabria via Pietro Bucci 87036 Arcavacata di Rende Cs Italy

Department of Chemistry University of Warwick Coventry CV4 7AL U K

Institute of Biophysics Czech Academy of Sciences CZ 61200 Brno Czech Republic

State Key Laboratory of Vaccines for Infectious Diseases Xiang An Biomedicine Laboratory National Innovation Platform for Industry Education Integration in Vaccine Research School of Public Health Xiamen University Xiamen361102 China

Zobrazit více v PubMed

Coluccia M., Natile G.. Trans-Platinum Compounds in Cancer Therapy. Anti-Cancer Agents Med. Chem. 2007;7:111–123. doi: 10.2174/187152007779314080. PubMed DOI

Kalinowska-Lis U., Ochocki J., Matlawska-Wasowska K.. Trans Geometry in Platinum Antitumor Complexes. Coord. Chem. Rev. 2008;252(12–14):1328–1345. doi: 10.1016/j.ccr.2007.07.015. DOI

Zhao S., Yang Z., Jiang G., Huang S., Bian M., Lu Y., Liu W.. An Overview of Anticancer Platinum N-Heterocyclic Carbene Complexes. Coord. Chem. Rev. 2021;449:214217. doi: 10.1016/j.ccr.2021.214217. DOI

Rottenberg S., Disler C., Perego P.. The Rediscovery of Platinum-based Cancer Therapy. Nat. Rev. Cancer. 2021;21:37–50. doi: 10.1038/s41568-020-00308-y. PubMed DOI

Alderden R. A., Hall M. D., Hambley T. W.. The Discovery and Development of Cisplatin. J. Chem. Educ. 2006;83(5):728–734. doi: 10.1021/ed083p728. DOI

Wang K., Lu J., Li R.. The Events That Occur When Cisplatin Encounters Cells. Coord. Chem. Rev. 1996;151:53–88. doi: 10.1016/S0010-8545(96)90195-2. DOI

Pérez J. M., Fuertes M. A., Alonso C., Navarro-Ranninger C.. Current Status of the Development of Trans-Platinum Antitumor Drugs. Crit. Rev. Oncol. Hematol. 2000;35(2):109–120. doi: 10.1016/S1040-8428(00)00053-6. PubMed DOI

Heringova P., Woods J., Mackay F. S., Kasparkova J., Sadler P. J., Brabec V.. Transplatin Is Cytotoxic When Photoactivated: Enhanced Formation of DNA Cross-Links. J. Med. Chem. 2006;49(26):7792–7798. doi: 10.1021/jm0606692. PubMed DOI

Ohndorf U. M., Rould M. A., He Q., Pabo C. O., Lippard S. J.. Basis for Recognition of Cisplatin-Modified DNA by High-Mobility-Group Proteins. Nature. 1999;399:708–712. doi: 10.1038/21460. PubMed DOI

Natile, G. ; Coluccia, M. .

Kelland L. R., Barnard C. F. J., Mellish K. J., Jones M., Goddard P. M., Valenti M., Bryant A., Murrer B. A., Harrap K. R.. A Novel Trans-Platinum Coordination Complex Possessing in Vitro and in Vivo Antitumor Activity. Cancer Res. 1994;54(21):5618–5622. PubMed

Arandjelovic S., Tesic Z., Radulovic S.. Trans-Platinum Complexes with Promising Antitumor Properties. Med. Chem. Rev. 2005;2(5):415–422. doi: 10.2174/156720305774330476. DOI

Aris S. M., Farrell N. P.. Towards Antitumor Active Trans-Platinum Compounds. Eur. J. Inorg. Chem. 2009;10:1293–1302. doi: 10.1002/ejic.200801118. PubMed DOI PMC

Quiroga A. G.. Non-Classical Structures Among Current Platinum Complexes with Potential as Antitumor Drugs. Curr. Top. Med. Chem. 2011;11(21):2613–2622. doi: 10.2174/156802611798040723. PubMed DOI

Radulovic S., Tesic Z., Manic S.. Trans-Platinum Complexes as Anticancer Drugs: Recent Developments and Future Prospects. Curr. Med. Chem. 2002;9(17):1611–1618. doi: 10.2174/0929867023369376. PubMed DOI

Cai L., Yu C., Ba L., Liu Q., Qian Y., Yang B., Gao C.. Anticancer Platinum-Based Complexes with Non-Classical Structures. Appl. Organomet. Chem. 2018;32(4):e4228. doi: 10.1002/aoc.4228. DOI

Xu Z., Wang Z., Deng Z., Zhu G.. Recent Advances in the Synthesis, Stability, and Activation of Platinum­(IV) Anticancer Prodrugs. Coord. Chem. Rev. 2021;442:213991. doi: 10.1016/j.ccr.2021.213991. DOI

Gibson D.. Platinum­(IV) Anticancer Agents; Are We En Route to the Holy Grail or to a Dead End? J. Inorg. Biochem. 2021;217:111353. doi: 10.1016/j.jinorgbio.2020.111353. PubMed DOI

Štarha P., Křikavová R.. Platinum­(IV) and Platinum­(II) Anticancer Complexes with Biologically Active Releasable Ligands. Coord. Chem. Rev. 2024;501:215578. doi: 10.1016/j.ccr.2023.215578. DOI

Karges J.. Chemical and Photophysical Triggers for the Reduction of Pt­(IV) Prodrugs for Anticancer Therapy. ChemNanoMat. 2023;9(11):e202300295. doi: 10.1002/cnma.202300295. DOI

Shi H., Marchi R., Sadler P. J.. Advances in the Design of Photoactivatable Metallodrugs: Excited State Metallomics. Angew. Chem., Int. Ed. 2025;64:e202423335. doi: 10.1002/anie.202423335. PubMed DOI

O’Neill C. F., Ormerod M. G., Robertson D., Titley J. C., Cumber-Walsweer Y., Kelland L. R.. Apoptotic and Non-Apoptotic Cell Death Induced by Cis and Trans Analogues of a Novel Ammine­(Cyclohexylamine)­Dihydroxodichloroplatinum­(IV) Complex. Br. J. Cancer. 1996;74(7):1037–1045. doi: 10.1038/bjc.1996.486. PubMed DOI PMC

Lemma K., Shi T., Elding L. I.. Kinetics and Mechanism for Reduction of the Anticancer Prodrug Trans, Trans, Trans-[PtCl2(OH)2(c-C6H11NH2)­(NH3)] (JM335) by Thiols. Inorg. Chem. 2000;39(8):1728–1734. doi: 10.1021/ic991351l. PubMed DOI

Kratochwil N. A., Guo Z., Murdoch P. S., Parkinson J. A., Bednarski P. J., Sadler P. J.. Electron-Transfer-Driven Trans-Ligand Labilization: A Novel Activation Mechanism for Pt­(IV) Anticancer Complexes. J. Am. Chem. Soc. 1998;120(32):8253–8254. doi: 10.1021/ja980393q. DOI

Kratochwil N. A., Zabel M., Range K. J., Bednarski P. J.. Synthesis and X-Ray Crystal Structure of Trans,Cis-[Pt­(OAc)2I2(En)]: A Novel Type of Cisplatin Analog That Can Be Photolyzed by Visible Light to DNA-Binding and Cytotoxic Species in Vitro. J. Med. Chem. 1996;39(13):2499–2507. doi: 10.1021/jm9509105. PubMed DOI

Kratochwil N. A., Bednarski P. J.. Relationships between reduction properties and cancer cell growth inhibitory activities of cis-dichloro- and cis-diiodo-Pt­(IV)-ethylenediamines. Arch. Pharm. Pharm. Med. Chem. 1999;332:279–285. doi: 10.1002/(SICI)1521-4184(19998)332:8<279::AID-ARDP279>3.0.CO;2-1. PubMed DOI

Shi H., Imberti C., Sadler P. J.. Diazido Platinum­(IV) Complexes for Photoactivated Anticancer Chemotherapy. Inorg. Chem. Front. 2019;6:1623–1638. doi: 10.1039/C9QI00288J. DOI

Shi H., Sadler P. J.. Advances in the Design of Photoactivated Platinum Anticancer Complexes. Adv. Inorg. Chem. 2022;80:95–127. doi: 10.1016/bs.adioch.2022.07.001. DOI

Mu M., Zhan J., Dai X., Gao H.. Research Progress of Azido-Containing Pt­(IV) Antitumor Compounds. Eur. J. Med. Chem. 2022;227:113927. doi: 10.1016/j.ejmech.2021.113927. PubMed DOI

Dai Z., Wang Z.. Photoactivatable Platinum-Based Anticancer Drugs: Mode of Photoactivation and Mechanism of Action. Molecules. 2020;25(21):5167. doi: 10.3390/molecules25215167. PubMed DOI PMC

Mackay F. S., Woods J. A., Moseley H., Ferguson J., Dawson A., Parsons S., Sadler P. J.. A Photoactivated Trans-Diammine Platinum Complex as Cytotoxic as Cisplatin. Chem.Eur. J. 2006;12(11):3155–3161. doi: 10.1002/chem.200501601. PubMed DOI

Farrer N. J., Woods J. A., Munk V. P., MacKay F. S., Sadler P. J.. Photocytotoxic Trans-Diam­(m)­Ine Platinum­(IV) Diazido Complexes More Potent than Their Cis Isomers. Chem. Res. Toxicol. 2010;23(2):413–421. doi: 10.1021/tx900372p. PubMed DOI PMC

Shi H., Clarkson G. J., Sadler P. J.. Tuning the Phototherapeutic Activity of Pt­(IV) Complexes for Bladder Cancer via Modification of Trans N-Heterocyclic Ligands. Inorg. Chem. Front. 2024;11(22):7898–7909. doi: 10.1039/D4QI01765J. DOI

Leitsch D.. A Review on Metronidazole: An Old Warhorse in Antimicrobial Chemotherapy. Parasitology. 2019;146(9):1167–1178. doi: 10.1017/S0031182017002025. PubMed DOI

Pehrson P., Bengtsson E.. Treatment of Non-Invasive Amoebiasis - A Comparison between Tinidazole and Metronidazole. Ann. Trop. Med. Parasitol. 1984;78(5):505–508. doi: 10.1080/00034983.1984.11811856. PubMed DOI

Skov K. A., Adomat H., Chaplin D. J., Farrell N. P.. Toxicity of [PtCl2(NH3)­L] in Hypoxia; L = Misonidazole or Metronidazole. Anticancer Drug Des. 1990;5(1):121–128. PubMed

Farrell N., Skov K. A.. Radiosensitizers Targeted to DNA Using Platinum. Synthesis, Characterisation, and DNA Binding of Cis-[PtCl2(NH3)­(Nitroimidazole)] J. Chem. Soc. Chem. Commun. 1987;13:1043–1044. doi: 10.1039/c39870001043. DOI

Spector D. V., Erofeev A. S., Gorelkin P. V., Vaneev A. N., Akasov R. A., Ul’Yanovskiy N. V., Nikitina V. N., Semkina A. S., Vlasova K. Y., Soldatov M. A., Trigub A. L., Skvortsov D. A., Finko A. V., Zyk N. V., Sakharov D. A., Majouga A. G., Beloglazkina E. K., Krasnovskaya O. O.. Electrochemical Detection of a Novel Pt­(IV) Prodrug with the Metronidazole Axial Ligand in the Hypoxic Area. Inorg. Chem. 2022;61(37):14705–14717. doi: 10.1021/acs.inorgchem.2c02062. PubMed DOI

Martin R. L.. Natural Transition Orbitals. J. Chem. Phys. 2003;118(11):4775–4777. doi: 10.1063/1.1558471. DOI

Butler J. S., Woods J. A., Farrer N. J., Newton M. E., Sadler P. J.. Tryptophan Switch for a Photoactivated Platinum Anticancer Complex. J. Am. Chem. Soc. 2012;134(40):16508–16511. doi: 10.1021/ja3074159. PubMed DOI

Escudero D., Heuser E., Meier R. J., Schäferling M., Thiel W., Holder E.. Unveiling Photodeactivation Pathways for a New Iridium­(III) Cyclometalated Complex. Chem.Eur. J. 2013;19(46):15639–15644. doi: 10.1002/CHEM.201301291. PubMed DOI

Escudero D., Thiel W.. Assessing the Density Functional Theory-Based Multireference Configuration Interaction (DFT/MRCI) Method for Transition Metal Complexes. J. Chem. Phys. 2014;140(19):194105. doi: 10.1063/1.4875810/350994. PubMed DOI

Mukherjee S., Bhatti G. K., Chhabra R., Reddy P. H., Bhatti J. S.. Targeting Mitochondria as a Potential Therapeutic Strategy against Chemoresistance in Cancer. Biomed. Pharmacother. 2023;160:114398. doi: 10.1016/j.biopha.2023.114398. PubMed DOI

Scaduto R. C., Grotyohann L. W.. Measurement of Mitochondrial Membrane Potential Using Fluorescent Rhodamine Derivatives. Biophys. J. 1999;76(1):469–477. doi: 10.1016/S0006-3495(99)77214-0. PubMed DOI PMC

Gonzalez V. M., Fuertes M. A., Alonso C., Perez J. M.. Is Cisplatin-Induced Cell Death Always Produced by Apoptosis? Mol. Pharmacol. 2001;59(4):657–663. doi: 10.1124/mol.59.4.657. PubMed DOI

Cohen S. M., Lippard S. J.. Cisplatin: From DNA Damage to Cancer Chemotherapy. Prog. Nucleic Acid Res. Mol. Biol. 2001;67:93–130. doi: 10.1016/S0079-6603(01)67026-0. PubMed DOI

Duan M., Ulibarri J., Liu K. J., Mao P.. Role of Nucleotide Excision Repair in Cisplatin Resistance. Int. J. Mol. Sci. 2020;21(23):9248. doi: 10.3390/ijms21239248. PubMed DOI PMC

Wootton C. A., Sanchez-Cano C., Lopez-Clavijo A. F., Shaili E., Barrow M. P., Sadler P. J., O’Connor P. B.. Sequence-Dependent Attack on Peptides by Photoactivated Platinum Anticancer Complexes. Chem. Sci. 2018;9(10):2733–2739. doi: 10.1039/C7SC05135B. PubMed DOI PMC

Du J., Wei Y., Zhao Y., Xu F., Wang Y., Zheng W., Luo Q., Wang M., Wang F.. A Photoactive Platinum­(IV) Anticancer Complex Inhibits Thioredoxin-Thioredoxin Reductase System Activity by Induced Oxidization of the Protein. Inorg. Chem. 2018;57(9):5575–5584. doi: 10.1021/acs.inorgchem.8b00529. PubMed DOI

Sun S., Shen J., Jiang J., Wang F., Min J.. Targeting Ferroptosis Opens New Avenues for the Development of Novel Therapeutics. Signal Transduct. Target. Ther. 2023;8:372. doi: 10.1038/s41392-023-01606-1. PubMed DOI PMC

Nie Q., Hu Y., Yu X., Li X., Fang X.. Induction and Application of Ferroptosis in Cancer Therapy. Cancer Cell Int. 2022;22:12. doi: 10.1186/s12935-021-02366-0. PubMed DOI PMC

Li J., Cao F., Yin H., liang, Huang Z., jian, Lin Z., tao, Mao N., Sun B., Wang G.. Ferroptosis: Past, Present and Future. Cell Death Dis. 2020;11(2):88. doi: 10.1038/s41419-020-2298-2. PubMed DOI PMC

Patel O. P. S., Jesumoroti O. J., Legoabe L. J., Beteck R. M.. Metronidazole-Conjugates: A Comprehensive Review of Recent Developments towards Synthesis and Medicinal Perspective. Eur. J. Med. Chem. 2021;210:112994. doi: 10.1016/j.ejmech.2020.112994. PubMed DOI

Lamp K. C., Freeman C. D., Klutman N. E., Lacy M. K.. Pharmacokinetics and Pharmacodynamics of the Nitroimidazole Antimicrobials. Clin. Pharmacokinet. 1999;36(5):353–373. doi: 10.2165/00003088-199936050-00004. PubMed DOI

Zhao Y., Farrer N. J., Li H., Butler J. S., McQuitty R. J., Habtemariam A., Wang F., Sadler, De P. J.. Novo Generation of Singlet Oxygen and Ammine Ligands by Photoactivation of a Platinum Anticancer Complex. Angew. Chem., Int. Ed. 2013;52(51):13633–13637. doi: 10.1002/anie.201307505. PubMed DOI PMC

Shi H., Kasparkova J., Soulié C., Clarkson G. J., Imberti C., Novakova O., Paterson M. J., Brabec V., Sadler P. J.. DNA-Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light. Chem.Eur. J. 2021;27(41):10711–10716. doi: 10.1002/CHEM.202101168. PubMed DOI PMC

Shi H., Romero-Canelón I., Hreusova M., Novakova O., Venkatesh V., Habtemariam A., Clarkson G. J., Song J.-I., Brabec V., Sadler P. J.. Photoactivatable Cell-Selective Dinuclear Trans-Diazidoplatinum­(IV) Anticancer Prodrugs. Inorg. Chem. 2018;57(22):14409–14420. doi: 10.1021/acs.inorgchem.8b02599. PubMed DOI PMC

Tai H. C., Brodbeck R., Kasparkova J., Farrer N. J., Brabec V., Sadler P. J., Deeth R. J.. Combined Theoretical and Computational Study of Interstrand DNA Guanine-Guanine Cross-Linking by Trans-[Pt­(Pyridine)2] Derived from the Photoactivated Prodrug Trans,Trans,Trans-[Pt­(N3)2(OH)2(Pyridine)2] Inorg. Chem. 2012;51(12):6830–6841. doi: 10.1021/ic3005745. PubMed DOI

Ara I., Forniés J., Fortuño C., Ibáñez S., Martín A., Mastrorilli P., Gallo V.. Unsymmetrical Platinum­(II) Phosphido Derivatives: Oxidation and Reductive Coupling Processes Involving Platinum­(III) Complexes as Intermediates. Inorg. Chem. 2008;47(19):9069–9080. doi: 10.1021/ic8011124. PubMed DOI

Wilson J. J., Lippard S. J.. Acetate-Bridged Platinum­(III) Complexes Derived from Cisplatin. Inorg. Chem. 2012;51(18):9852–9864. doi: 10.1021/ic301289j. PubMed DOI PMC

Westendorf A. F., Bodtke A., Bednarski P. J.. Studies on the Photoactivation of Two Cytotoxic Trans,Trans,Trans-Diazidodiaminodihydroxo-Pt­(IV) Complexes. Dalton Trans. 2011;40(19):5342–5351. doi: 10.1039/c0dt01485k. PubMed DOI

Shi H., Ward-Deitrich C., Ponte F., Sicilia E., Goenaga-Infante H., Sadler P. J.. Photosubstitution and Photoreduction of a Diazido Platinum­(IV) Anticancer Complex. Dalton Trans. 2024;53(31):13044–13054. doi: 10.1039/D4DT01587H. PubMed DOI

Bolitho E. M., Sanchez-Cano C., Shi H., Quinn P. D., Harkiolaki M., Imberti C., Sadler P. J.. Single-Cell Chemistry of Photoactivatable Platinum Anticancer Complexes. J. Am. Chem. Soc. 2021;143(48):20224–20240. doi: 10.1021/jacs.1c08630. PubMed DOI PMC

Steinke S. J., Piechota E. J., Loftus L. M., Turro C.. Acetonitrile Ligand Photosubstitution in Ru­(II) Complexes Directly from the 3MLCT State. J. Am. Chem. Soc. 2022;144(44):20177–20182. doi: 10.1021/jacs.2c07209. PubMed DOI

Xie Z., Cao B., Zhao J., Liu M., Lao Y., Luo H., Zhong Z., Xiong X., Wei W., Zou T.. Ion Pairing Enables Targeted Prodrug Activation via Red Light Photocatalysis: A Proof-of-Concept Study with Anticancer Gold Complexes. J. Am. Chem. Soc. 2024;146(12):8547–8556. doi: 10.1021/jacs.4c00408. PubMed DOI

Zhang Y., Doan B. T., Gasser G.. Metal-Based Photosensitizers as Inducers of Regulated Cell Death Mechanisms. Chem. Rev. 2023;123(16):10135–10155. doi: 10.1021/acs.chemrev.3c00161. PubMed DOI

Kuznetsov K. M., Cariou K., Gasser G.. Two in One: Merging Photoactivated Chemotherapy and Photodynamic Therapy to Fight Cancer. Chem. Sci. 2024;15(43):17760–17780. doi: 10.1039/D4SC04608K. PubMed DOI PMC

Bonnet S.. Ruthenium-Based Photoactivated Chemotherapy. J. Am. Chem. Soc. 2023;145(43):23397–23415. doi: 10.1021/jacs.3c01135. PubMed DOI PMC

Havrylyuk D., Hachey A. C., Fenton A., Heidary D. K., Glazer E. C.. Ru­(II) Photocages Enable Precise Control over Enzyme Activity with Red Light. Nat. Commun. 2022;13:3636. doi: 10.1038/s41467-022-31269-5. PubMed DOI PMC

Mitchell R. J., Havrylyuk D., Hachey A. C., Heidary D. K., Glazer E. C.. Photodynamic Therapy Photosensitizers and Photoactivated Chemotherapeutics Exhibit Distinct Bioenergetic Profiles to Impact ATP Metabolism. Chem. Sci. 2025;16(2):721–734. doi: 10.1039/D4SC05393A. PubMed DOI PMC

Mani A., Feng T., Gandioso A., Vinck R., Notaro A., Gourdon L., Burckel P., Saubaméa B., Blacque O., Cariou K., Belgaied J. E., Chao H., Gasser G.. Structurally Simple Osmium­(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy in the Near Infrared. Angew. Chem., Int. Ed. 2023;62(20):e202218347. doi: 10.1002/anie.202218347. PubMed DOI

Chettri A., Yang T., Cole H. D., Shi G., Cameron C. G., McFarland S. A., Dietzek-Ivanšić B.. Using Biological Photophysics to Map the Excited-State Topology of Molecular Photosensitizers for Photodynamic Therapy. Angew. Chem., Int. Ed. 2023;62(17):e202301452. doi: 10.1002/anie.202301452. PubMed DOI PMC