Anticancer study of heterobimetallic platinum(II)-ruthenium(II) and platinum(II)-rhodium(III) complexes with bridging dithiooxamide ligand

Abstract

Three heterobimetallic platinum (II)/ruthenium (II) and platinum (II)/rhodium (III) complexes, A: Pt{S–S2C2(NR)2H}{μ-S2C2(NR)2}-[Ru (p-cymene)Cl], R = isoamyl; B: Pt{S–S2C2(NR)2H}{μ-S2C2(NR)2}[Rh (phpy)2], R = isoamyl; C: [Pt{S–S2C2(NR)2H}{μ-S2C2(NR)2}-[Rh(C5Me5)Cl]], R = benzyl, were prepared from mononuclear complexes 1 and 2, 1: [Pt (H-isoamyl2DTO)2]; 2: [Pt (H-benzyl2DTO)2], DTO = dithiooxamide, by reaction of 1 or 2 with the corresponding chlorido-bridged dimers, [Rh(C5Me5)Cl (μ-Cl)]2, [Ru (p-cymene)Cl (μ-Cl)]2 or [Rh (phpy)2 (μ-Cl)]2, and then evaluated as anticancer agents for the inhibition of the three proteolytic activities of human 20S proteasome, one of the main target for cancer therapy. These complexes were also screened for the inhibition of a couple of human cathepsins known to be involved in metastatic processes. A-C turned out to be active towards these enzymes. In addition, they showed in vitro antiproliferative activity against neuroblastoma SH-SY5Y, melanoma SK-Mel-28, hepatocellular adenocarcinoma HepG2 and colorectal adenocarcinoma Caco-2 tumor cell lines, without any sign of cytotoxicity in primary human fibroblasts WI-38. Moreover, these complexes induced apoptosis in the former tumor cell line, as displayed by cytofluorimetric analyses. This study indicated that these compounds may represent valuable lead structures for the development of new anticancer agents.