A series of platinum(II) diiodido complexes containing 7-azaindole derivatives, having the general formula cis-[PtI2(naza)2] (1-8), has been prepared and thoroughly characterized, including X-ray structure analysis of cis-[PtI2(2Me4Claza)2]∙DMF (8∙DMF; 2Me4Claza = 2-methyl-4-chloro-7-azaindole). Complexes showed high in vitro cytotoxicity against nine human cancer cell lines (IC50 ranging from 0.4 to 12.8 μM), including the cisplatin-resistant ovarian cancer cell line (A2780R; IC50 = 1.0-3.5 μM). The results of in vivo testing, using the L1210 lymphocytic leukaemia model, at the equimolar doses of Pt with cisplatin (2 mg/kg) confirmed the activity of complex 8 comparable to cisplatin. From the mechanistic point of view, evaluated ex vivo by Western blot analyses on the samples of isolated tumour tissues, the treatment of the animals with complex 8, contrary to cisplatin, decreased the levels of tumour suppressor p53 and increased significantly the amount of intracellular anti-apoptotic protein MCL-1L (37 kDa). Additionally, the active form of caspase 3 was significantly elevated in the sample of tumour tissues treated with complex 8, indicating that the activation of p53-independent cell-death pathway was initiated. The light and electron microscopy observations of the cancerous tissues revealed necrosis as a dominant mechanism of cell death, followed by scarce signs of apoptosis. The additional results (e.g. in vitro interaction experiments with selected biomolecules, cell cycle perturbations, gel electrophoretic studies on pUC19 plasmid DNA) supported the hypothesis that the complexes might be involved in the mechanism of action quite different from cisplatin.

Department of Cell Biology and Genetics and Regional Centre of Advanced Technologies and Materials Department of Inorganic Chemistry Faculty of Science Palacký University in Olomouc Olomouc Czech Republic

Department of Human Pharmacology and Toxicology Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Department of Inorganic Chemistry and Regional Centre of Advanced Technologies and Materials Faculty of Science Palacký University in Olomouc Olomouc Czech Republic

See more in PubMed

Wheate NJ, Walker S, Craig GE, Oun R. The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans. 2010; 39: 8113–8127. 10.1039/c0dt00292e PubMed DOI

Kelland L. The resurgence of platinum-based cancer chemotherapy. Nature Rev Cancer. 2007; 7: 573–584. PubMed

Cleare MJ, Hoeschele JD. Studies on the antitumour activity of group VIII transition Metal complexes. Part I. Platinum(II) complexes. Bioinorg Chem. 1973; 2: 187–210.

Aggarwal SK, Broomhead JA, Fairlie DP, Whitehouse MW. Platinum drugs: Combined anti-lymphoproliferative and nephrotoxicity assay in rats. Cancer Chemother Pharmacol. 1980; 4: 249–258. PubMed

Arandjelovic S, Tesic Z, Juranic Z, Radulovic S, Vrvic M, Potkonjak B, et al. Antiproliferative activity of some cis-/trans-platinum(II) complexes on HeLa cells. J Exp Clin Cancer Res. 2002; 21: 519–526. PubMed

Marzo T, Pillozzi S, Hrabina O, Kasparkova J, Brabec V, Arcangeli A, et al. cis-PtI2(NH3)2: a reappraisal. Dalton Trans. 2015; 44: 14896–14905. 10.1039/c5dt01196e PubMed DOI

Margiotta N, Natile G, Capitelli F, Fanizzi FP, Boccarelli A, De Rinaldis P, et al. Sterically hindered complexes of platinum(II) with planar heterocyclic nitrogen donors. A novel complex with 1-methyl-cytosine has a spectrum of activity different from cisplatin and is able of overcoming acquired cisplatin resistance. J Inorg Biochem. 2006; 100: 1849–1857. 10.1016/j.jinorgbio.2006.07.010 PubMed DOI

Margiotta N, Savino S, Gandin V, Marzano C, Natile G. Monofunctional platinum(II) complexes with potent tumour cell growth inhibitory activity: the effect of a hydrogen-bond donor/acceptor N-heterocyclic ligand. ChemMedChem. 2014; 9: 1161–1168. 10.1002/cmdc.201402028 PubMed DOI

Messori L, Casini A, Gabbiani C, Michelucci E, Cubo L, Rios-Luci C, et al. Cytotoxic profile and peculiar reactivity with biomolecules of a novel “rule-breaker” iodidoplatinum(II) complex. ACS Med Chem Lett. 2010; 1: 381–385. 10.1021/ml100081e PubMed DOI PMC

Messori L, Cubo L, Gabbiani C, Alvarez-Valdes A, Michelucci E, Pieraccini G, et al. Reactivity and biological properties of a series of cytotoxic PtI2(amine)2 complexes, either cis or trans configured. Inorg Chem. 2012; 51: 1717–1726. 10.1021/ic202036c PubMed DOI

Savic A, Filipovic L, Arandjelovic S, Dojcinovic B, Radulovic S, Sabo TJ, et al. Synthesis, characterization and cytotoxic activity of novel platinum(II) iodido complexes. Eur J Med Chem. 2014; 82: 372–384. 10.1016/j.ejmech.2014.05.060 PubMed DOI

Skander M, Retailleau P, Bourrie B, Schio L, Mailliet P, Marinetti A. N-heterocyclic carbene-amine Pt(II) complexes, a new chemical space for the development of platinum-based anticancer drugs. J Med Chem. 2010; 53: 2146–2154. 10.1021/jm901693m PubMed DOI

Chardon E, Dahm G, Guichard G, Bellemin-Laponnaz S. Derivatization of preformed platinum N-heterocyclic carbene complexes with amino acid and peptide ligands and cytotoxic activities toward human cancer cells. Organometallics. 2012; 31: 7618–7621.

Chtchigrovsky M, Eloy L, Jullien H, Saker L, Segal-Bendirdjian E, Poupon J, et al. Antitumour trans-N-heterocyclic carbene-amine-Pt(II) complexes: synthesis of dinuclear species and exploratory investigations of DNA binding and cytotoxicity mechanisms. J Med Chem. 2013; 56: 2074–2086. 10.1021/jm301780s PubMed DOI

Messori L, Marzo T, Gabbiani C, Valdes AA, Quiroga AG, Merlino A. Peculiar features in the crystal structure of the adduct formed between cis-PtI2(NH3)2 and hen egg white lysozyme. Inorg Chem. 2013; 52: 13827–13829. 10.1021/ic402611m PubMed DOI

Štarha P, Trávníček Z, Popa A, Popa I, Muchová T, Brabec V. How to modify 7-azaindole to form cytotoxic Pt(II) complexes: highly in vitro anticancer effective cisplatin derivatives involving halogeno-substituted 7-azaindole. J Inorg Biochem. 2012; 115: 57–63. 10.1016/j.jinorgbio.2012.05.006 PubMed DOI

Štarha P, Hošek J, Vančo J, Dvořák Z, Suchý P, Popa I, et al. Pharmacological and molecular effects of platinum(II) complexes involving 7-azaindole derivatives. PLoS ONE. 2014; 9: e90341 10.1371/journal.pone.0090341 PubMed DOI PMC

Štarha P, Dvořák Z, Trávníček Z. Highly and broad-spectrum in vitro antitumour active cis-dichloridoplatinum(II) complexes with 7-azaindoles. PLoS ONE. 2015; 10: e0136338 10.1371/journal.pone.0136338 PubMed DOI PMC

New EJ, Roche C, Madawala R, Zhang JZ, Hambley TW. Fluorescent analogues of quinoline reveal amine ligand loss from cis and trans platinum(II) complexes in cancer cells. J Inorg Biochem. 2009; 103: 1120–1125. 10.1016/j.jinorgbio.2009.05.005 PubMed DOI

Pracharova J, Saltarella T, Radosova Muchova T, Scintilla S, Novohradsky V, Novakova O, et al. Novel antitumour cisplatin and transplatin derivatives containing 1-methyl-7-azaindole: synthesis, characterization, and cellular responses. J Med Chem. 2015; 58: 847–859. 10.1021/jm501420k PubMed DOI

Štarha P, Trávníček Z, Dvořák Z, Radošová-Muchová T, Prachařová J, Vančo J, et al. Potentiating effect of UVA irradiation on anticancer activity of carboplatin derivatives involving 7-azaindoles. PLoS ONE. 2015; 10: e0123595 10.1371/journal.pone.0123595 PubMed DOI PMC

Oxford Diffraction, CrysAlis RED and CrysAlis CCD Software (Ver. 1.171.33.52), Oxford Diffraction Ltd., Abingdon, Oxfordshire, UK.

Sheldrick GM. Crystal structure refinement with SHELXL. Acta Crystallogr. C. 2015; 71: 3–8. PubMed PMC

Brandenburg K, Diamond Version 4.0.3., Crystal Impact GbR, Bonn, Germany, 2015.

Macrae CF, Bruno IJ, Chisholm JA, Edgington PR, McCabe P, Pidcock E, et al. Mercury CSD 2.0—new features for the visualization and investigation of crystal structures. J Appl Crystallogr. 2008; 41: 466–470.

Hissler M, Connick WB, Geiger DK, McGarrah JE, Lipa D, Lachicotte RJ, et al. Platinum diimine bis(acetylide) complexes: synthesis, characterization, and luminescence properties. Inorg Chem. 2000; 39: 447–457. PubMed

Vardevanyan PO, Antonyan AP, Parsadanyan MA, Davtyan HG, Karapetyan AT. The binding of ethidium bromide with DNA: interaction with single- and double-stranded structures. Exp Mol Med. 2003; 35: 527–533. 10.1038/emm.2003.68 PubMed DOI

Dhara SC. A rapid method for the synthesis of cis-[Pt(NH3)2Cl2]. Indian J Chem. 1970; 8: 193–194.

Gulyaeva N, Zaslavsky A, Lechner P, Chlenov M, Chait A, Zaslavsky B. Relative hydrophobicity and lipophilicity of β-blockers and related compounds as measured by aqueous two-phase partitioning, octanol-buffer partitioning, and HPLC. Eur J Pharm Sci. 2002; 17: 81–93. PubMed

Tetko IV, Varbanov HP, Galanski M, Talmaciu M, Platts JA, Raverag M, et al. Prediction of logP for Pt(II) and Pt(IV) complexes: comparison of statistical and quantum-chemistry based approaches. J Inorg Biochem. 2016; 156: 1–13. 10.1016/j.jinorgbio.2015.12.006 PubMed DOI

Štarha P, Marek J, Trávníček Z. Cisplatin and oxaliplatin derivatives involving 7-azaindole: structural characterisations. Polyhedron. 2012; 33: 404–409.

Tessier C, Rochon FD. Multinuclear NMR study and crystal structures of complexes of the types cis- and trans-Pt(Ypy)2X2, where Ypy = pyridine derivative and X = Cl and I. Inorg Chim. Acta. 1999; 295: 25–38.

Sakai K, Yokoyama Y, Masaoka S. cis-Dichlorobis(4-methylpyridine-κN)platinum(II). Acta Cryst. 2007; E63: m97–m99.

Shi Y, Tang B, Yu PW, Tang B, Hao YX, Lei X, et al. Autophagy protects against oxaliplatin-induced cell death via ER stress and ROS in Caco-2 cells. PLoS ONE. 2012; 7: e51076 10.1371/journal.pone.0051076 PubMed DOI PMC

de Mier-Vinue J, Lorenzo J, Montana AM, Moreno V, Aviles FX. Synthesis, DNA interaction and cytotoxicity studies of cis-{[1,2-bis(aminomethyl)cyclohexane]dihalo}platinum(II) complexes. J Inorg Biochem. 2008; 102: 973–987. 10.1016/j.jinorgbio.2007.12.026 PubMed DOI

Holford J, Sharp SY, Murrer BA, Abrams M, Kelland LR. In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473. Br J Cancer. 1998; 77: 366–373. PubMed PMC

Sharp SY, O’Neill CF, Rogers PM, Boxall FE; Kelland LR. Retention of activity by the new generation platinum agent AMD0473 in four human tumour cell lines possessing acquired resistance to oxaliplatin. Eur J Cancer. 2002; 38: 2309–2315. PubMed

Ossipov K, Scaffidi-Domianello YY, Seregina IF, Galanski M, Keppler BK, Timerbaev AR, et al. Inductively coupled plasma mass spectrometry for metallodrug development: albumin binding and serum distribution of cytotoxic cis- and trans-isomeric platinum(II) complexes. J Inorg Biochem. 2014; 137: 40–45. 10.1016/j.jinorgbio.2014.04.008 PubMed DOI

Bartel C, Bytzek AK, Scaffidi-Domianello YY, Grabmann G, Jakupec MA, Hartinger CG, et al. Cellular accumulation and DNA interaction studies of cytotoxic trans-platinum anticancer compounds. J Biol Inorg Chem. 2012; 17: 465–474. 10.1007/s00775-011-0869-5 PubMed DOI

Ormerod M, O’Neill C, Robertson D, Kelland L, Harrap K. cis-Diamminedichloroplatinum(II)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines. Cancer Chemother Pharmacol. 1996; 37: 463–471. 10.1007/s002800050413 PubMed DOI

MacKeigan JP, Collins TS, Ting JPY. MEK inhibition enhances paclitaxel-induced tumour apoptosis. J Biol Chem. 2000; 275: 38953–38956. 10.1074/jbc.C000684200 PubMed DOI

Wu S, Wang X, He Y, Zhu Z, Zhu C, Guo Z. A monofunctional trinuclear platinum complex with steric hindrance demonstrates strong cytotoxicity against tumour cells. J Inorg Biochem. 2014; 139: 77–84. 10.1016/j.jinorgbio.2014.06.006 PubMed DOI

Muchová T, Prachařová J, Štarha P, Olivová R, Vrána O, Benešová B, et al. Insight into the toxic effects of cis-dichloridoplatinum(II) complexes containing 7-azaindole halogeno derivatives in tumour cells. J Biol Inorg Chem. 2013; 18: 579–589. 10.1007/s00775-013-1003-7 PubMed DOI

Onoa G Bibiana, Cervantes G, Moreno V, Prieto M José. Study of the interaction of DNA with cisplatin and other Pd(II) and Pt(II) complexes by atomic force microscopy. Nucleic Acids Res. 1998; 26: 1473–1480. PubMed PMC

Berners-Price SJ. Activating platinum anticancer complexes with visible light. Angew. Chem. Int. Ed. 2011; 50: 804–805. PubMed

Roy S, Maheswari PU, Lutz M, Spek AL, den Dulk H, Barends S, et al. DNA cleavage and antitumour activity of platinum(II) and copper(II) compounds derived from 4-methyl-2-N-(2-pyridylmethyl)aminophenol: spectroscopic, electrochemical and biological investigation. Dalton Trans. 2009; 48: 10846–10860. PubMed

Butour JL, Macquet JP. Differentiation of DNA-platinum complexes by fluorescence. The use of an intercalating dye as a probe. Eur J Biochem. 1977; 78: 455–463. PubMed

Pasternack RF, Caccam M, Keogh B, Stephenson TA, Williams AP, Gibbst EJ. Long-range fluorescence quenching of ethidium ion by cationic porphyrins in the presence of DNA. J Am Chem Soc. 1991; 113: 6835–6840.

Wanga K, Stringfellow S, Dong S, Jiao Y, Yu H. Synthesis and fluorescence study of 7-azaindole in DNA oligonucleotides replacing a purine base. Spectrochim. Acta A. 2002; 58: 2595–2603. PubMed PMC

Sbovata S Mazzega, Bettio F, Mozzon M, Bertani R, Venzo A, Benetollo F, et al. Cisplatinum and transplatinum complexes with benzyliminoether ligands; synthesis, characterization, structure-activity relationships, and in vitro and in vivo antitumour efficacy. J Med Chem. 2007; 50: 4775–4784. 10.1021/jm070426p PubMed DOI

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

Ploner C, Kofler R, Villunger A. Noxa: at the tip of the balance between life and death. Oncogene. 2009; 27: 84–92. PubMed PMC

Suntharalingam K, Wilson JJ, Lin W, Lippard SJ. A dual-targeting, p53-independent, apoptosis-inducing platinum(II) anticancer complex, [Pt(BDI(QQ))]Cl. Metallomics. 2014; 6: 437–443. 10.1039/c3mt00364g PubMed DOI PMC

Novel cis-Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action

In vitro anticancer active cis-Pt(II)-diiodido complexes containing 4-azaindoles