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

Abstract

Twelve Pt(II) complexes with cis-PtP₂S₂ 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-PtP₂S₂ 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-PtP₂S₂ 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-PtP₂S₂ compounds strongly suggests that these compounds will undergo specific activation within the cellular environment.