While ruthenium arene complexes have been widely investigated for their medicinal potential, studies on homologous compounds containing a tridentate tris(1-pyrazolyl)methane ligand are almost absent in the literature. Ruthenium(II) complex 1 was obtained by a modified reported procedure; then, the reactions with a series of organic molecules (L) in boiling alcohol afforded novel complexes 2-9 in 77-99% yields. Products 2-9 were fully structurally characterized. They are appreciably soluble in water, where they undergo partial chloride/water exchange. The antiproliferative activity was determined using a panel of human cancer cell lines and a noncancerous one, evidencing promising potency of 1, 7, and 8 and significant selectivity toward cancer cells. The tested compounds effectively accumulate in cancer cells, and mitochondria represent a significant target of biological action. Most notably, data provide convincing evidence that the mechanism of biological action is mediated by the inhibiting of mitochondrial calcium intake.

Czech Academy of Sciences Institute of Biophysics Kralovopolska 135 CZ 61265 Brno Czech Republic

Department of Chemistry and Industrial Chemistry University of Pisa Via G Moruzzi 13 1 56124 Pisa Italy

Department of Industrial Chemistry Toso Montanari University of Bologna Viale Risorgimento 4 1 40136 Bologna Italy

Faculty of Science Department of Biochemistry Masaryk University Kamenice 5 CZ 62500 Brno Czech Republic

Faculty of Science Department of Biophysics Palacky University in Olomouc Slechtitelu 27 CZ 78371 Olomouc Czech Republic

Zobrazit více v PubMed

Anthony E. J.; Bolitho E. M.; Bridgewater H. E.; Carter O. W. L.; Donnelly J. M.; Imberti C.; Lant E. C.; Lermyte F.; Needham R. J.; Palau M.; Sadler P. J.; Shi H.; Wang F.-X.; Zhang W.-Y.; Zhang Z. Metallodrugs are unique: opportunities and challenges of discovery and development. Chem. Sci. 2020, 11, 12888–12917. 10.1039/D0SC04082G. PubMed DOI PMC

Marloye M.; Berger G.; Gelbcke M.; Dufrasne F. A survey of the mechanisms of action of anticancer transition metal complexes. Future Med. Chem. 2016, 8, 2263–2286. 10.4155/fmc-2016-0153. PubMed DOI

Boros E.; Dyson P. J.; Gasser G. Classification of metal-based drugs according to their mechanisms of action. Chem 2020, 6, 41–60. 10.1016/j.chempr.2019.10.013. PubMed DOI PMC

Liu Y.-C.; Miller J. J.. Platinum-Based Anticancer Drugs. In Encyclopedia of Inorganic and Bioinorganic Chemistry; Wiley, 2011.

Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg. Chem. 2019, 88, 10292510.1016/j.bioorg.2019.102925. PubMed DOI

Riddell I. A.; Lippard S. J. Cisplatin and Oxaliplatin: Our current understanding of their actions. Met. Ions Life Sci. 2018, 18, 1–42. PubMed

Oun R.; Moussa Y. E.; Wheate N. J. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans. 2018, 47, 6645–6653. 10.1039/C8DT00838H. PubMed DOI

Siddik Z. H. Cisplatin mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22, 7265–7279. 10.1038/sj.onc.1206933. PubMed DOI

Peng K.; Liang B.-B.; Liu W.; Mao Z.-W. What blocks more anticancer platinum complexes from experiment to clinic: major problems and potential strategies from drug design perspectives. Coord. Chem. Rev. 2021, 449, 21421010.1016/j.ccr.2021.214210. DOI

Qi L.; Luo Q.; Zhang Y.; Jia F.; Zhao Y.; Wang F. Advances in toxicological research of the anticancer drug cisplatin. Chem. Res. Toxicol. 2019, 32, 1469–1486. 10.1021/acs.chemrestox.9b00204. PubMed DOI

Murray B. S.; Dyson P. J. Recent progress in the development of organometallics for the treatment of cancer. Current Opinion. Chem. Biol. 2020, 56, 28–34. PubMed

Hanif M.; Hartinger C. G. Anticancer metallodrugs: where is the next cisplatin?. Future Med. Chem. 2018, 10, 615–617. 10.4155/fmc-2017-0317. PubMed DOI

Mjos K. D.; Orvig C. Metallodrugs in medicinal inorganic chemistry. Chem. Rev. 2014, 114, 4540–4563. 10.1021/cr400460s. PubMed DOI

Thota S.; Rodrigues D. A.; Crans D. C.; Barreiro E. J. Ru(II) compounds: next-generation anticancer metallotherapeutics?. J. Med. Chem. 2018, 61, 5805–5821. 10.1021/acs.jmedchem.7b01689. PubMed DOI

Zeng L.; Gupta P.; Chen Y.; Wang E.; Ji L.; Chao H.; Chen Z.-S. The development of anticancer ruthenium(II) complexes: from single molecule compounds to nanomaterials. Chem. Soc. Rev. 2017, 46, 5771–5804. 10.1039/C7CS00195A. PubMed DOI PMC

Alessio E. Thirty years of the drug candidate NAMI-A and the myths in the field of ruthenium anticancer compounds: a personal perspective. Eur. J. Inorg. Chem. 2017, 2017, 1549–1560. 10.1002/ejic.201600986. DOI

Trondl R.; Heffeter P.; Kowol C. R.; Jakupec M. A.; Berger W.; Keppler B. K. NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application. Chem. Sci. 2014, 5, 2925–2932. 10.1039/C3SC53243G. DOI

Murray B. S.; Babak M. V.; Hartinger C. G.; Dyson P. J. The development of RAPTA compounds for the treatment of tumors. Coord. Chem. Rev. 2016, 306, 86–114. 10.1016/j.ccr.2015.06.014. DOI

Rausch M.; Dyson P. J.; Nowak-Sliwinska P. Recent Considerations in the application of RAPTA-C for cancer treatment and perspectives for its combination with immunotherapies. Adv. Therap. 2019, 2, 190004210.1002/adtp.201900042. DOI

Steel T. R.; Walsh F.; Wieczorek-Błauz A.; Hanif M.; Hartinger C. G. Monodentately-coordinated bioactive moieties in multimodal half-sandwich organoruthenium anticancer agents. Coord. Chem. Rev. 2021, 439, 21389010.1016/j.ccr.2021.213890. DOI

Singh A. K.; Pandey D. S.; Xu Q.; Braunstein P. Recent advances in supramolecular and biological aspects of arene ruthenium(II) complexes. Coord. Chem. Rev. 2014, 270–271, 31–56. 10.1016/j.ccr.2013.09.009. DOI

Swaminathan S.; Haribabu J.; Balakrishnan N.; Vasanthakumar P.; Karvembu R. Piano stool Ru(II)-arene complexes having three monodentate legs: A comprehensive review on their development as anticancer therapeutics over the past decade. Coord. Chem. Rev. 2022, 459, 21440310.1016/j.ccr.2021.214403. DOI

Chotard F.; Malacea-Kabbara R.; Balan C.; Bodio E.; Picquet M.; Richard P.; Ponce-Vargas M.; Fleurat-Lessard P.; Le Gendre P. Atom transfer radical addition catalyzed by ruthenium-arene complexes bearing a hybrid phosphine-diene ligand. Organometallics 2018, 37, 812–820. 10.1021/acs.organomet.7b00851. DOI

Biancalana L.; Pampaloni G.; Zacchini S.; Marchetti F. Synthesis, characterization and behavior in water/DMSO solution of Ru(II) arene complexes with bioactive carboxylates. J. Organomet. Chem. 2018, 869, 201–211. 10.1016/j.jorganchem.2018.05.020. DOI

Egger A. E.; Hartinger C. G.; Renfrew A. K.; Dyson P. J. Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand. J. Biol. Inorg. Chem. 2010, 15, 919–927. 10.1007/s00775-010-0654-x. PubMed DOI

Bugarcic T.; Habtemariam A.; Stepankova J.; Heringova P.; Kasparkova J.; Deeth R. J.; Johnstone R. D. L.; Prescimone A.; Parkin A.; Parsons S.; Brabec V.; Sadler P. J. The contrasting chemistry and cancer cell cytotoxicity of bipyridine and bipyridinediol ruthenium(II) arene complexes. Inorg. Chem. 2008, 47, 11470–11486. 10.1021/ic801361m. PubMed DOI

Biancalana L.; Batchelor L. K.; Ciancaleoni G.; Zacchini S.; Pampaloni G.; Dyson P. J.; Marchetti F. Versatile coordination of acetazolamide to ruthenium(II) p-cymene complexes and preliminarycytotoxicity studies. Dalton Trans. 2018, 47, 9367–9384. 10.1039/C8DT01555D. PubMed DOI

Bigmore H. R.; Lawrence S. C.; Mountford P.; Tredget C. S. Coordination, organometallic and related chemistry of tris(pyrazolyl)methane ligands. Dalton Trans. 2005, 635–651. 10.1039/b413121e. PubMed DOI

Reger D. L. Tris(pyrazolyl) methane ligands: the neutral analogs of tris(pyrazolyl) borate ligands. Comments Inorg. Chem. 1999, 21, 1–28. 10.1080/02603599908020413. DOI

Semeniuc R. F.; Reger D. L. Metal complexes of multitopic, third generation poly(pyrazolyl)-methane ligands: multiple coordination arrangements. Eur. J. Inorg. Chem. 2016, 2016, 2253–2271. 10.1002/ejic.201600116. DOI

Bhambri S.; Tocher D. A. Synthesis and characterisation of ruthenium(II) arene complexes containing κ3- and κ2-poly(pyrazolyl)borates and methanes. J. Chem. Soc. Dalton Trans. 1997, 18, 3367–3372. 10.1039/a702674i. DOI

Muñoz-Molina J. M.; Belderrain T. R.; Perez P. J. Group 11 tris(pyrazolyl) methane complexes: structural features and catalytic applications. Dalton Trans. 2019, 48, 10772–10781. 10.1039/C9DT01661A. PubMed DOI

Martins L. M. D. R. S.; Pombeiro A. J. L. Tris(pyrazol-1-yl)methane metal complexes for catalytic mild oxidative functionalizations of alkanes, alkenes and ketones. Coord. Chem. Rev. 2014, 265, 74–88. 10.1016/j.ccr.2014.01.013. DOI

Martins L. M. D. R. S. C-scorpionate complexes: Ever young catalytic tools. Coord. Chem. Rev. 2019, 396, 89–102. 10.1016/j.ccr.2019.06.009. DOI

Waywell P.; Gonzalez V.; Gill M. R.; Adams H.; Meijer A. J. H. M.; Williamson M. P.; Thomas J. A. Structure of the complex of [Ru(tpm)(dppz)py]2+ with a B-DNA oligonucleotide-a single-substituent binding switch for a metallo-Intercalator. Chem. - Eur. J. 2010, 16, 2407–2417. 10.1002/chem.200901758. PubMed DOI

Foxon S. P.; Metcalfe C.; Adams H.; Webb M.; Thomas J. A. Electrochemical and photophysical properties of DNA metallo-intercalators containing the ruthenium(II) tris(1-pyrazolyl)methane unit. Inorg. Chem. 2007, 46, 409–416. 10.1021/ic0607134. PubMed DOI

Walker J. M.; McEwan A.; Pycko R.; Tassotto M. L.; Gottardo C.; Th’ng J.; Wang R.; Spivak G. J. [Tris(pyrazolyl)methane]ruthenium complexes capable of inhibiting cancer cell growth. Eur. J. Inorg. Chem. 2009, 2009, 4629–4633. 10.1002/ejic.200900766. DOI

Field L. D.; Messerle B. A.; Soler L.; Buys I. E.; Hambley T. W. Polypyrazolylmethane complexes of ruthenium. J. Chem. Soc., Dalton Trans. 2001, 1959–1965. 10.1039/b103939n. DOI

Shaw A. P.; Ryland B. L.; Norton J. R.; Buccella D.; Moscatelli A. Electron exchange involving a sulfur-stabilized ruthenium radical cation. Inorg. Chem. 2007, 46, 5805–5812. 10.1021/ic700580u. PubMed DOI

Miguel S.; Diez J.; Gamasa M. P.; Lastra M. E. Synthesis and structural features of new ruthenium(II) complexes containing the scorpionate ligands tris(pyrazol-1-yl)methanesulfonate (Tpms) and tris(pyrazol-1-yl)methane (Tpm). Eur. J. Inorg. Chem. 2011, 2011, 4745–4755. 10.1002/ejic.201100621. DOI

Belli R. G.; Wu Y.; Ji H.; Joshi A.; Yunker L. P. E.; McIndoe J. S.; Rosenberg L. Competitive ligand exchange and dissociation in Ru indenyl complexes. Inorg. Chem. 2019, 58, 747–755. 10.1021/acs.inorgchem.8b02915. PubMed DOI

Lentz D.; Michael-Schulz H. Syntheses, structure determination and reactions of phosphine substituted derivatives of (μ3-FC)2Fe3(CO)9. Z. Anorg. Allg. Chem. 1992, 618, 111–120. 10.1002/zaac.19926180120. DOI

Albano V. G.; Busetto L.; Marchetti F.; Monari M.; Zacchini S.; Zanotti V. Synthesis and characterization of new diiron and diruthenium μ-aminocarbyne complexes containing terminal S-, P- and C-ligands. Z. Naturforsch. B 2007, 62, 427–438. 10.1515/znb-2007-0317. DOI

Bresciani G.; Biancalana L.; Pampaloni G.; Zacchini S.; Ciancaleoni G.; Marchetti F. A comprehensive analysis of the metal–nitrile bonding in an organo-diiron system. Molecules 2021, 26, 7088.10.3390/molecules26237088. PubMed DOI PMC

Baker P. K.; Harman M. E.; Hursthouse M. B.; Karaulov A. I.; Lavery A. J.; Malik K. M. A.; Muldoon D. J.; Shawcross A. Nitrile exchange reactions of MI2(CO)3(NCMe)2. X-ray crystal structures of mixed-ligand seven-coordinate complexes. J. Organomet. Chem. 1995, 494, 205–221. 10.1016/0022-328X(95)05405-E. DOI

Su B.-K.; Liu Y.-H.; Peng S.-M.; Liu S.-T. An anthyridine-based pentanitrogen donor switches from mono- to tetradentate with Pd(II) Ions. Organometallics 2021, 40, 4110–4119. 10.1021/acs.organomet.1c00569. DOI

Biancalana L.; Ciancaleoni G.; Zacchini S.; Pampaloni G.; Marchetti F. Carbonyl-isocyanide mono-substitution in [Fe2Cp2(CO)4]: A re-visitation. Inorg. Chim. Acta 2020, 517, 120181.

Faraone F.; Piraino P.; Marsala V.; Sergi S. Tricarbonyldichloro(thiocarbonyl)ruthenium(II) and related complexes: synthesis and reactions to give aminomercaptocarbene and isocyanide complexes. J. Chem. Soc., Dalton Trans. 1977, 859–861. 10.1039/DT9770000859. DOI

Bruce M. I.; Wallis R. C. Cyclopentadienyl-ruthenium and -osmium chemistry. XIII* Some complexes containing isonitrile ligands. Aust. J. Chem. 1981, 34, 209–213. 10.1071/CH9810209. DOI

Bartalucci N.; Belpassi L.; Marchetti F.; Pampaloni G.; Zacchini S.; Ciancaleoni G. Ubiquity of cis-halide to isocyanide direct interligand interaction in organometallic complexes. Inorg. Chem. 2018, 57, 14554–14563. 10.1021/acs.inorgchem.8b02088. PubMed DOI

Wilson D. C.; Nelson J. H. Reactions of ruthenium(II) tris(pyrazolyl)borate and tris(pyrazolyl)methane complexes with diphenylvinylphosphine and 3,4-dimethyl-1-phenylphosphole. J. Organomet. Chem. 2003, 682, 272–289. 10.1016/j.jorganchem.2003.07.010. DOI

Niu Y.; Han F.; Zhang Q.; Xie T.; Lu L.; Li S.; Xia H. Off/On Fluorescent chemosensors for organotin halides based on binuclear ruthenium complexes. Angew. Chem., Int. Ed. 2013, 52, 5599–5603. 10.1002/anie.201209549. PubMed DOI

Cuervo D.; Menéndez-Pedregal E.; Díez J.; Gamasa M. P. Mononuclear ruthenium(II) complexes bewring the (S,S)-iPr-pybox ligand. J. Organomet. Chem. 2011, 696, 1861–1867. 10.1016/j.jorganchem.2011.02.025. DOI

Tubaro C.; Bertinazzo D.; Monticelli M.; Saoncella O.; Volpe A.; Basato M.; Badocco D.; pastore P.; Graiff C.; Venzo A. Synthesis and reactivity of cationic Bis(N-heterocyclic dicarbene) ruthenium(II) complexes. Eur. J. Inorg. Chem. 2014, 2014, 1524–1532. 10.1002/ejic.201301583. DOI

Cotton F. A.; Yokochi A. Three reactions of Ru25+ compounds of the passlewheel type that lead to cleavage of the Ru-Ru bond. Inorg. Chim. Acta 1998, 275-276, 557–561. 10.1016/S0020-1693(98)00136-4. DOI

Scolaro C.; Hartinger C. G.; Allardyce C. S.; Keppler B. K.; Dyson P. J. Hydrolysis study of the bifunctional antitumour compound RAPTA-C, [Ru(η6-p-cymene)Cl2(pta)]. J. Inorg. Biochem. 2008, 102, 1743–1748. 10.1016/j.jinorgbio.2008.05.004. PubMed DOI

Wang F.; Habtemariam A.; van der Geer E. P. L.; Fernández R.; Melchart M.; Deeth R. J.; Aird R.; Guichard S.; Fabbiani F. P. A.; Lozano-Casal P.; Oswald I. D. H.; Jodrell D. I.; Parsons S.; Sadler P. J. Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 18269–18274. 10.1073/pnas.0505798102. PubMed DOI PMC

Scolaro C.; Bergamo A.; Brescacin Delfino L.; Delfino R.; Cocchietto M.; Laurenczy G.; Geldbach T. J.; Sava G.; Dyson P. J. In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. J. Med. Chem. 2005, 48, 4161–4171. 10.1021/jm050015d. PubMed DOI

Meier-Menches S. M.; Gerner C.; Berger W.; Hartinger C. G.; Keppler B. K. Structure–activity relationships for ruthenium and osmium anticancer agents – towards clinical development. Chem. Soc. Rev. 2018, 47, 909–928. 10.1039/C7CS00332C. PubMed DOI

Biancalana L.; Batchelor L. K.; Dyson P. J.; Zacchini S.; Schoch S.; Pampaloni G.; Marchetti F. α-Diimine homologues of cisplatin: synthesis, speciation in DMSO/water and cytotoxicity. New J. Chem. 2018, 42, 17453–17463. 10.1039/C8NJ04195D. DOI

Biancalana L.; Batchelor L. K.; Funaioli T.; Zacchini S.; Bortoluzzi M.; Pampaloni G.; Dyson P. J.; Marchetti F. α-Diimines as versatile, derivatizable ligands in ruthenium(II) p-cymene anticancer complexes. Inorg. Chem. 2018, 57, 6669–6685. 10.1021/acs.inorgchem.8b00882. PubMed DOI

Kostrhunova H.; Petruzzella E.; Gibson D.; Kasparkova J.; Brabec V. A new anticancer Pt(IV) prodrug that acts by mechanisms involving DNA damage and different epigenetic effects. Chem.–Eur. J. 2019, 25, 5235–5245. 10.1002/chem.201805626. PubMed DOI

Rothemund M.; Bär S. I.; Rehm T.; Kostrhunova H.; Brabec V.; Schobert R. Antitumoral effects of mitochondria-targeting neutral and cationic cis-[bis(1,3-dibenzylimidazol-2-ylidene)Cl(L)]Pt(II) complexes. Dalton Trans. 2020, 49, 8901–8910. 10.1039/D0DT01664K. PubMed DOI

Marchetti F.; Di Nicola C.; Pettinari R.; Pettinari C.; Aiello I.; La Deda M.; Candreva A.; Morelli S.; De Bartolo L.; Crispini A. Zinc(II) complexes of acylpyrazolones decorated with a cyclohexyl group display antiproliferative activity against human breast cancer cells. Eur. J. Inorg. Chem. 2020, 2020, 1027–1039. 10.1002/ejic.201900775. DOI

Akhmetova V. R.; Akhmadiev N. S.; Abdullin M. F.; Dzhemileva L. U.; Dyakonov V. A. Synthesis of new N,N-Pd(Pt) complexes based on sulfanyl pyrazoles, and investigation of their in vitro anticancer activity. RSC Adv. 2020, 10, 15116–15123. 10.1039/C9RA09783J. PubMed DOI PMC

Zanda E.; Busto N.; Biancalana L.; Zacchini S.; Biver T.; Garcia B.; Marchetti F. Anticancer and antibacterial potential of robust Ruthenium(II) arene complexes regulated by choice of α-diimine and halide ligands. Chem. Biol. Interact. 2021, 344, 10952210.1016/j.cbi.2021.109522. PubMed DOI

Sáez R.; Lorenzo J.; Prieto M. J.; Font-Bardia M.; Calvet T.; Omeñaca N.; Vilaseca M.; Moreno V. Influence of PPh3 moiety in the anticancer activity of new organometallic ruthenium complexes. J. Inorg. Biochem. 2014, 136, 1–12. 10.1016/j.jinorgbio.2014.03.002. PubMed DOI

Zeng L.; Gupta P.; Chen Y.; Wang E.; Ji L.; Chao H.; Chen Z.-S. The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials. Chem. Soc. Rev. 2017, 46, 5771–5804. 10.1039/C7CS00195A. PubMed DOI PMC

Lin K.; Zhao Z.-Z.; Bo H.-B.; Hao X.-J.; Wang J.-Q. Applications of ruthenium complex in tumor diagnosis and therapy. Front. Pharmacol. 2018, 9, 132310.3389/fphar.2018.01323. PubMed DOI PMC

Parveen S.; Hanif M.; Movassaghi S.; Sullivan M. P.; Kubanik M.; Shaheen M. A.; Söhnel T.; Jamieson S. M. F.; Hartinger C. G. Cationic Ru(η6-p-cymene) complexes of 3-hydroxy-4-pyr(id)ones – lipophilic triphenylphosphine as co-ligand is key to highly stable and cytotoxic anticancer agents. Eur. J. Inorg. Chem. 2017, 2017, 1721–1727. 10.1002/ejic.201601163. DOI

Biancalana L.; Zacchini S.; Ferri N.; Lupo M. G.; Pampaloni G.; Marchetti F. Tuning the cytotoxicity of ruthenium(II) para cymene complexes by mono-substitution at a triphenylphosphine/phenoxydiphenylphosphine ligand. Dalton Trans. 2017, 46, 16589–16604. 10.1039/C7DT03385K. PubMed DOI

Schoch S.; Batchelor L. K.; Funaioli T.; Ciancaleoni G.; Zacchini S.; Braccini S.; Chiellini F.; Biver T.; Pampaloni G.; Dyson P. J.; Marchetti F. Diiron complexes with a bridging functionalized allylidene ligand: synthesis, structural aspects, and cytotoxicity. Organometallics 2020, 39, 361–373. 10.1021/acs.organomet.9b00813. DOI

Eastman A. Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays. Oncotarget 2017, 8, 8854–8866. 10.18632/oncotarget.12673. PubMed DOI PMC

Mirzayans R.; Andrais B.; Murray D. Do multiwell plate high throughput assays measure loss of cell viability following exposure to genotoxic agents?. Int. J. Mol. Sci. 2017, 18, 1679.10.3390/ijms18081679. PubMed DOI PMC

Riddell I. A.; Lippard S. J.. Metallo-Drugs: Development and Action of Anticancer Agents; Sigel A.; Sigel H.; Freisinger E.; Sigel R. K. O., Eds.; De Gruyter: Berlin/Munich/Boston, 2018; pp 1–42.

Novohradsky V.; Zerzankova L.; Stepankova J.; Vrana O.; Raveendran R.; Gibson D.; Kasparkova J.; Brabec V. New insights into the molecular and epigenetic effects of antitumor Pt(IV)-valproic acid conjugates in human ovarian cancer cells. Biochem. Pharmacol. 2015, 95, 133–144. 10.1016/j.bcp.2015.04.003. PubMed DOI

Novohradsky V.; Zanellato I.; Marzano C.; Pracharova J.; Kasparkova J.; Gibson D.; Gandin V.; Osella D.; Brabec V. Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates. Sci. Rep. 2017, 7, 375110.1038/s41598-017-03864-w. PubMed DOI PMC

Brabec V.; Kasparkova J. Ruthenium coordination compounds of biological and biomedical significance. DNA binding agents. Coord. Chem. Rev. 2018, 376, 75–94. 10.1016/j.ccr.2018.07.012. DOI

Johnson N. P.; Butour J.-L.; Villani G.; Wimmer F. L.; Defais M.; Pierson V.; Brabec V.. Metal Antitumor Compounds: The Mechanism of Action of Platinum Complexes. In Ruthenium and Other Non-Platinum Metal Complexes in Cancer Chemotherapy, Progress in Clinical Biochemistry and Medicine; Springer, 1989; Vol. 10, pp 1–24.

Brabec V.; Hrabina O.; Kasparkova J. Cytotoxic platinum coordination compounds. DNA binding agents. Coord. Chem. Rev. 2017, 351, 2–31. 10.1016/j.ccr.2017.04.013. DOI

Abassi Y. A.; Xi B.; Zhang W. F.; Ye P. F.; Kirstein S. L.; Gaylord M. R.; Feinstein S. C.; Wang X. B.; Xu X. Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects. Chem. Biol. 2009, 16, 712–723. 10.1016/j.chembiol.2009.05.011. PubMed DOI PMC

Novohradsky V.; Yellol J.; Stuchlikova O.; Santana M. D.; Kostrhunova H.; Yellol G.; Kasparkova J.; Bautista D.; Ruiz J.; Brabec V. Organoruthenium complexes with C∧N ligands are highly potent cytotoxic agents that act by a new mechanism of action. Chem. - Eur. J. 2017, 23, 15294–15299. 10.1002/chem.201703581. PubMed DOI

Novohradsky V.; Zerzankova L.; Stepankova J.; Kisova A.; Kostrhunova H.; Liu Z.; Sadler P. J.; Kasparkova J.; Brabec V. A dual-targeting, apoptosis-inducing organometallic half-sandwich iridium anticancer complex. Metallomics 2014, 6, 1491–1501. 10.1039/C4MT00112E. PubMed DOI

Tan Q.; Yan X.; Song L.; Yi H.; Li P.; Sun G.; Yu D.; Li L.; Zeng Z.; Guo Z. Induction of mitochondrial dysfunction and oxidative damage by antibiotic drug doxycycline enhances the responsiveness of glioblastoma to chemotherapy. Med. Sci. Monit. 2017, 23, 4117–4125. 10.12659/MSM.903245. PubMed DOI PMC

Dong L.; Neuzil J. Targeting mitochondria as an anticancer strategy. Cancer Commun. 2019, 39, 63.10.1186/s40880-019-0412-6. PubMed DOI PMC

Lin Y.-T.; Lin K.-H.; Huang C.-J.; Wei A.-C. MitoTox: a comprehensive mitochondrial toxicity database. BMC Bioinf. 2021, 22, 36910.1186/s12859-021-04285-3. PubMed DOI PMC

Shen L.; Wen N.; Xia M.; Zhang Y. U.; Liu W.; Xu Y. E.; Sun L. Calcium efflux from the endoplasmic reticulum regulates cisplatin-induced apoptosis in human cervical cancer HeLa cells. Oncol. Lett. 2016, 11, 2411–2419. 10.3892/ol.2016.4278. PubMed DOI PMC

Giorgi C.; Agnoletto C.; Bononi A.; Bonora M.; De Marchi E.; Marchi S.; Missiroli S.; Patergnani S.; Poletti F.; Rimessi A.; Suski J. M.; Wieckowski M. R.; Pinton P. Mitochondrial calcium homeostasis as potential target for mitochondrial medicine. Mitochondrion 2012, 12, 77–85. 10.1016/j.mito.2011.07.004. PubMed DOI PMC

Sterea A. M.; El Hiani Y.. The Role of Mitochondrial Calcium Signaling in the Pathophysiology of Cancer Cells. In Calcium Signaling: Advances in Experimental Medicine and Biology; Islam M., Ed.; Springer, 2020; Vol. 1131. PubMed

Graier W. F.; Malli R. Mitochondrial calcium: a crucial hub for cancer cell metabolism?. Transl. Cancer Res. 2017, 6, S1124–S1127. 10.21037/tcr.2017.08.28. DOI

Dejos C.; Gkika D.; Cantelmo A. R. The two-way relationship between calcium and metabolism in cancer. Front. Cell Dev. Biol. 2020, 8, 57374710.3389/fcell.2020.573747. PubMed DOI PMC

Romero-Garcia S.; Prado-Garcia H. Mitochondrial calcium: transport and modulation of cellular processes in homeostasis and cancer. Int. J. Oncol. 2019, 54, 1155–1167. 10.3892/ijo.2019.4696. PubMed DOI

Nathan S. R.; Wilson J. J. Synthesis and evaluation of a ruthenium-based mitochondrial calcium uptake inhibitor. J. Vis. Exp. 2017, 128, 5652710.3791/56527. PubMed DOI PMC

de J García-Rivas G.; Carvajal K.; Correa F.; Zazueta C. Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br. J. Pharmacol. 2006, 149, 829–837. 10.1038/sj.bjp.0706932. PubMed DOI PMC

Woods J. J.; Lovett J.; Lai B.; Harris H. H.; Wilson J. J. Redox stability controls the cellular uptake and activity of ruthenium-based inhibitors of the mitochondrial calcium uniporter. Angew. Chem., Int. Ed. 2020, 59, 1433–785. 10.1002/anie.202000247. PubMed DOI

Woods J. J.; Nemani N.; Shanmughapriya S.; Kumar A.; Zhang M. Q.; Nathan S. R.; Thomas M.; Carvalho E.; Ramachandran K.; Srikantan S.; Stathopulos P. B.; Wilson J. J.; Madesh M. A selective and cell-permeable mitochondrial calcium uniporter (MCU) inhibitor preserves mitochondrial bioenergetics after hypoxia/reoxygenation injury. ACS Cent. Sci. 2019, 5, 153–166. 10.1021/acscentsci.8b00773. PubMed DOI PMC

Wang H. G.; Pathan N.; Ethell I. M.; Krajewski S.; Yamaguchi Y.; Shibasaki F.; McKeon F.; Bobo T.; Franke T. F.; Reed J. C. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999, 284, 339–343. 10.1126/science.284.5412.339. PubMed DOI

Carafoli E.; Molinari M. Calpain: a protease in search of a function?. Biochem. Biophys. Res. Commun. 1998, 247, 193–203. 10.1006/bbrc.1998.8378. PubMed DOI

Høyer-Hansen M.; Bastholm L.; Szyniarowski P.; Campanella M.; Szabadkai G.; Farkas T.; Bianchi K.; Fehrenbacher N.; Elling F.; Rizzuto R.; Stenfeldt Mathiasen I.; Jäättelä M. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol. Cell 2007, 25, 193–205. 10.1016/j.molcel.2006.12.009. PubMed DOI

Zanoni M.; Piccinini F.; Arienti C.; Zamagni A.; Santi S.; Polico R.; Bevilacqua A.; Tesei A. 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci. Rep. 2016, 6, 1910310.1038/srep19103. PubMed DOI PMC

Thoma C. R.; Zimmermann M.; Agarkova I.; Kelm J. M.; Krek W. 3D cell culture systems modeling tumor growth determinants in cancer target discovery. Adv. Drug Delivery Rev. 2014, 69–70, 29–41. 10.1016/j.addr.2014.03.001. PubMed DOI

Wernitznig D.; Kiakos K.; Del Favero G.; Harrer N.; Machat H.; Osswald A.; Jakupec M. A.; Wernitznig A.; Sommergruber W.; Keppler B. K. First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro. Metallomics 2019, 11, 1044–1048. 10.1039/c9mt00051h. PubMed DOI

Ravi M.; Paramesh V.; Kaviya S. R.; Anuradha E.; Solomon F.D.P. 3D cell culture systems: advantages and applications. J. Cell. Physiol. 2015, 230, 16–26. 10.1002/jcp.24683. PubMed DOI

Reger D. L.; Grattan T.; Brown K. J.; et al. Syntheses of tris(pyrazolyl)methane ligands and {[tris(pyrazolyl)methane]Mn(CO)3}SO3CF3 complexes: comparison of ligand donor properties. J. Organomet. Chem. 2000, 607, 120–128. 10.1016/S0022-328X(00)00290-4. DOI

Menges F.″Spectragryph - optical spectroscopy software″, Version 1.2.5, @ 2016-2017, http://www.effemm2.de/spectragryph.

Fulmer G. R.; Miller A. J. M.; Sherden N. H.; Gottlieb H. E.; Nudelman A.; Stoltz B. M.; Bercaw J. E.; Goldberg K. I. NMR chemical shifts of trace impurities: common laboratory solvents, organics, and gases in deuterated solvents relevant to the organometallic chemist. Organometallics 2010, 29, 2176–2179. 10.1021/om100106e. DOI

Willker W.; Leibfritz D.; Kerssebaum R.; Bermel W. Gradient selection in inverse heteronuclear correlation spectroscopy. Magn. Reson. Chem. 1993, 31, 287–292. 10.1002/mrc.1260310315. DOI

Jutand A. The use of conductivity measurements for the characterization of cationic palladium(II) complexes and for the determination of kinetic and thermodynamic data in palladium-catalyzed reactions. Eur. J. Inorg. Chem. 2003, 2003, 2017–2040. 10.1002/ejic.200300069. DOI

Geary W. J. The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coord. Chem. Rev. 1971, 7, 81–122. 10.1016/S0010-8545(00)80009-0. DOI

Sheldrick G. M. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3–8. 10.1107/S2053229614024218. PubMed DOI PMC

Flack H. D. On enantiomorph-polarity estimation. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39, 876–881. 10.1107/S0108767383001762. DOI

Spek A. L. Single-crystal structure validation with the program PLATON. J. Appl. Crystallogr. 2003, 36, 7–13. 10.1107/S0021889802022112. DOI

Spek A. L. Structure validation in chemical crystallography. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 148–155. 10.1107/S090744490804362X. PubMed DOI PMC

Rundlöf T.; Mathiasson M.; Bekiroglu S.; Hakkarainen B.; Bowden T.; Arvidsson T. Survey and qualification of internal standards for quantification by 1H NMR spectroscopy. J. Pharm. Biomed. Anal. 2010, 52, 645–651. 10.1016/j.jpba.2010.02.007. PubMed DOI

Rice N. M.; Irving H. M. N. H.; Leonard M. A. Nomenclature for liquid-liquid distribution (solvent extraction) (IUPAC Recommendations 1993). Pure Appl. Chem. 1993, 65, 2373–2396. 10.1351/pac199365112373. DOI

Dearden J. C.; Bresnen G. M. The measurement of partition coefficients. Quant. Struct.-Act. Relat. 1988, 7, 133–144. 10.1002/qsar.19880070304. DOI

Currie D. J.; Lough C. E.; Silver R. F.; Holmes H. L. Partition coefficients of some conjugated heteroenoid compounds and 1,4-naphthoquinones. Can. J. Chem. 1966, 44, 1035–1043. 10.1139/v66-154. DOI

Westcott C. C.pH Measurements; Academic Press: New York, 1978.

Covington A. K.; Paabo M.; Robinson R. A.; Bates R. G. Use of the glass electrode in deuterium oxide and the relation between the standardized pD (paD) scale and the operational pH in heavy water. Anal. Chem. 1968, 40, 700–706. 10.1021/ac60260a013. DOI

A Novel Substituted Benzo[g]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent

Anticancer Potential of Diruthenium Complexes with Bridging Hydrocarbyl Ligands from Bioactive Alkynols