Molecular, cellular and pharmacological effects of platinum(II) diiodido complexes containing 9-deazahypoxanthine derivatives: A group of broad-spectrum anticancer active agents

Abstract

The platinum(II) iodido complexes 1–5 of the general formula cis-[PtI2(Ln)2], where Ln stands for O-substituted 9-deazahypoxanthine derivatives, were prepared and thoroughly characterized by various techniques, including multinuclear 1D and 2D NMR spectroscopy. The complexes were screened for their anticancer potential in vitro on ten human cancer cell lines, concretely breast adenocarcinoma (MCF7), osteosarcoma (HOS), lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), malignant melanoma (G-361), prostate carcinoma (22Rv1, PC-3), hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780) and cisplatin-resistant ovarian carcinoma (A2780R). The complexes exhibited significant wide-spectrum anticancer activity in vitro against all the employed cell lines, with IC50≈0.5–24.0μM. Very good correlation between the lipophilicity parameter log P and IC50 values of anticancer activity in vitro were obtained by simple QSAR analysis. The most lipophilic complexes 2, 4 and 5 showed the best results, as they reached the sub-micromolar IC50 values against the A2780 and A2780R sub-lines, with the best result equal 0.5±0.1μM on A2780 for complex 5. The in vivo testing of the representative complexes 1, 4 and 5 (applied at the same dose of Pt as 2mg/kg dose of cisplatin) on a L1210 leukaemia model revealed their positive effect on the prolongation of the mean survival time, even if it was lower than that of cisplatin. The 1H NMR interaction study revealed the ability of complexes to interact with glutathione (GSH) and 5′-guanosine monophosphate (GMP) and overall higher stability of the complexes 1–5 as compared to cisplatin. The electrospray-ionization mass spectrometry experiments with complex 1 identified the formation of a rich collection of hydrolytic species in water-containing media after 24h and the interaction intermediates with sulfur-containing biomolecule l-cysteine, but not with the reduced glutathione at physiologically relevant concentration levels.