Structure, solution chemistry, antiproliferative actions and protein binding properties of non-conventional platinum(ii) compounds with sulfur and phosphorus donors

摘要

Twelve Pt(ii) complexes with cis-PtP_2S_2 pharmacophores (where P2 refers to two monodentate or one bidentate phosphane ligand and S2 is a dithiolato ligand) were prepared, characterized and evaluated as potential antiproliferative agents. The various compounds were first studied from the structural point of view; afterward, their solubility properties as well as their solution behaviour were analyzed in detail. Antiproliferative properties were specifically evaluated against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin. For comparison purposes similar studies were carried out on four parent cis-dichloro bisphosphane Pt(ii)complexes. On the whole, the cis-PtP2S 2 compounds displayed significant antiproliferative properties while the cis-PtP2Cl2 (cis-dichloro bisphosphane Pt(ii)) compounds revealed quite poor biological performances. To gain further insight into the molecular mechanisms of these bisphosphane Pt(ii) compounds, the reactions of selected complexes against the model protein cytochrome c were investigated by ESI-MS and their adduct formation explored. A relevant reactivity with cyt c was obtained only for cis-PtP2Cl2 compounds, whereas cis-PtP_2S_2 compounds turned out to be nearly unreactive. The obtained results are interpreted and discussed in the frame of the current knowledge of anticancer platinum compounds and their structure-activity-relationships. The observation of appreciable antiproliferative effects for the relatively inert cis-PtP2S 2 compounds strongly suggests that these compounds will undergo specific activation within the cellular environment.