Dichlorido-platinum(II) complexes with kinetin derivatives as promising cytotoxic agents avoiding resistance of cancer cells: Contrasting results between cisplatin and oxaliplatin analogues

Abstract

With the aim to study the anticancer potential and compare the influence of different leaving groups, dichlorido and oxalato (ox) platinum(II) complexes involving di- and tri-substituted derivatives of a plant hormone kinetin (N6-furfuryladenine; Ln) were prepared: cis-[PtCl2(L1)2]·H2O (1), trans-[PtCl2(L1)2] (1a), cis-[PtCl2(L2)2]·0.75H2O (2), and [Pt(L1)2(ox)] (3), [Pt(L2)2(ox)] (4), with 2-chloro-N6-furfuryl-9-isopropyladenine (L1) and 2-chloro-N6-(5-methylfurfuryl)-9-isopropyladenine (L2). The complexes were structurally characterized by elemental and thermal analyses, FT-IR and 1H, 13C, 15N and 195Pt NMR spectroscopy, ESI+ mass spectrometry, conductivity measurements as well as single crystal X-ray diffraction (for 1). The Ln carrier ligands act as monodentate N-donors coordinated to the platinum(II) centre, which reveals a slightly distorted square-planar geometry. All the prepared complexes were screened for their in vitro cytotoxicity against breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines. This preliminary study identified only the cis-dichlorido-Pt(II) complexes 1, 2 as cytotoxic agents. These two complexes were thus further evaluated for in vitro cytotoxicity against malignant melanoma (G-361), cervix epitheloid carcinoma (HeLa), cisplatin sensitive (A2780) and resistant (A2780R) ovarian carcinoma human cancer cell lines. Most importantly, the obtained results showed that the cis-[PtCl2(Ln)2]·xH2O complexes were able to circumvent cisplatin resistance in A2780R cells while additionally being significantly more cytotoxic against A2780 than cisplatin, as demonstrated by the resistance factors IC50(A2780R)/IC50(A2780) equal to 0.87 for 1; 0.48 for 2 as compared to 2.25 for cisplatin. The complexes were furthermore comparably active against HOS, MCF7, G-361 cells as cisplatin. In order to address the contrasting cytotoxic results of the cisplatin (1, 2) and oxaliplatin (3, 4) analogues, their possible fate in the physiological environment, focusing on the hydrolytic stability and interactions with glutathione and 5′-guanosine monophosphate, was studied by means of 1H NMR spectroscopy.