Platinacycles Containing a Primary Amine Platinum(II) Compounds for Treating Cisplatin-Resistant Cancers by Oxidant Therapy

Abstract

Cisplatin is an efficient anticancer drug, but its effects are often lost after several chemotherapy cycles, showing important secondary effects. For these reasons, new anticancer agents, with different coordination properties and mechanisms of action, are needed. Here we describe the reaction of 2-phenylaniline with cis-[PtCl2(dmso)(2)] and sodium acetate to afford a cycloplatinated compound 2 and the synthesis and some biological studies of 3-6 (two neutral and two ionic compounds): [PtCl(C-N)(L)], C-N cycloplatinated 2-phenylaniline with L = PPh3(3) or P(4-FC6H4)(3) (4) and [Pt(C-N)(L-L)]Cl with L-L = Ph2PCH2CH2Ph2(5) or (C6F5)(2)PCH2-CH2(C6F5)(2) (6). Ionic platinacycles 5 and 6 show a greater antiproliferative activity than that of cisplatin in human lung, breast, and colon cancer cell lines (A-549, MDA-MB-231 and MCF-7, and HCT-116), a remarkable result given the fact that they do not show covalent interaction with DNA. 5 and 6 have also been found able to oxidize NADH by a catalytic process prod- oducing H2O2 as ROS. The activity of these complexes to generate ROS seems to be the key factor to explain their potent anticancer activity; it should be noted that platinum(II) complexes showing biocatalytic activity for hydride transfer from NADH have not been described so far. Ionic complex 6 shows low affinity to some target proteins; the presence of perfluoroaromatic rings seems to hinder its interaction with some biomolecules.