Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity

The first examples of Pt complexes of the well known anti-epilepsy drug and histone deacetylase inhibitor, valproic acid (VPA), are reported. Reaction of the Pt(II) am(m)ine precursors trans-[PtCl 2(NH 3)(py)] and trans-[PtCl 2(py) 2] with silver nitrate and subsequently sodium valproate gave trans-[Pt(VPA −1H) 2(NH 3)(py)] and trans-[Pt(VPA −1H) 2(py) 2], respectively. The valproato ligands in both complexes are bound to the Pt(II) centres via the carboxylato functionality and in a monodentate manner. The X-ray crystal structure of trans-[Pt(VPA −1H) 2(NH 3)(py)] is described. Replacement of the dichlorido ligands in trans-[PtCl 2(py) 2] and trans-[PtCl 2(NH 3)(py)] by valproato ligands (VPA −1H) to yield trans-[Pt(VPA −1H) 2(py) 2] and trans-[Pt(VPA −1H) 2(NH 3)(py)] respectively, significantly enhanced cytotoxicity against A2780 (parental) and A2780 cisR (cisplatin resistant) ovarian cancer cells. The mutagenicity of trans-[Pt(VPA −1H) 2(NH 3)(py)] and trans-[Pt(VPA −1H) 2(py) 2] was determined using the Ames test and is also reported. We report novel trans-Pt planar am(m)mine complexes of valproic acid, a histone deacetylase inhibitor and potential anti-cancer agent. [Display omitted]