Synthesis, characterization and antiproliferative activity on mesothelioma cell lines of bis(carboxylato)platinum(iv) complexes based on picoplatin

Abstract

The synthesis and characterization of a series of picoplatin-based (picoplatin = [PtCl₂(mpy)(NH₃)], mpy = 2-methylpyridine), Pt(IV) complexes with axial carboxylato ligands of increasing length are reported. The synthesis is based on the oxidation with hydrogen peroxide of picoplatin to give the cis,cis,trans-[PtCl₂(mpy)(NH₃)(OH)₂] intermediate and then its transformation into the dicarboxylato complexes cis,cis,trans-[PtCl₂(mpy)(NH₃)(RCOO)₂] (R = CH₃(CH₂)_n, n = 0–4) with the corresponding anhydride. Pt(IV) complexes with n = 0–2 were selected to be tested on four malignant pleural mesothelioma (MPM) cell lines, on human mesothelial cells (HMC), and on the cisplatin-sensitive ovarian A2780 cell line along with cisplatin as a metallo-drug reference. In general, the longer the axial chain, the more cytotoxic and selective the Pt(IV) complex is. Pt(IV) analogs show good activity on the MPM cell lines, approaching or in some case bypassing that of cisplatin and represent quite promising drug candidates for the treatment of tumors whose chemoresistance is mainly based on glutathione overexpression, such as MPM.