Roscovitine-based CDK inhibitors acting as N-donor ligands in the platinum(II) oxalato complexes: Preparation, characterization and in vitro cytotoxicity

Abstract

The reactions of potassium bis(oxalato)platinate dihydrate with two molar equivalents of the potent adenine-based cyclin-dependent kinase inhibitor 2-(1-ethyl-2-hydroxyethylamino)-N6-(benzyl)-9-isopropyladenine ( Roscovitine; Ros) and its benzyl-substituted analogues, i.e. 2-(1-ethyl-2-hydroxyethylamino)-N6-(2-methoxybenzyl)-9-isopropyladenine (2 OMeRos), 2-(1-ethyl-2-hydroxyethylamino)-N6-(3-methoxybenzyl)-9-isopropyladenine (3 OMeRos) and 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (4 OMeRos), were performed and the [Pt(ox)(Ros) 2]·¾H 2O ( 1), [Pt(ox)(2 OMeRos) 2]·H 2O ( 2), [Pt(ox)( 3OMeRos) 2]·½H 2O ( 3) and [Pt(ox)( 4OMeRos) 2]·¾H 2O ( 4) platinum(II) oxalato complexes were obtained. The methods of the elemental analysis, IR, Raman and NMR spectroscopy, ESI + mass spectrometry, molar conductivity measurement and TG/DTA thermal analysis were performed to characterize the obtained products. The complexes 1– 4 involve tetracoordinated central Pt(II) atom with one bidentate-coordinated oxalate dianion (ox) and two monodentate adenine-based molecules ( nRos), thus giving the square-planar geometry around the metal centre with a PtN 2O 2 donor set. In vitro cytotoxic activity of the complexes against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was evaluated. All the tested complexes exceeded the in vitro cytotoxicity of cisplatin and oxaliplatin against HeLa, A2780cis and, except for 2, also against HOS cancer cells. The complex 1 was also tested for its cytotoxicity in primary cultures of human hepatocytes and it was not found to be hepatotoxic up to the concentration of 50.0 μM.