title: Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity.
abstract: 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.
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland. dgriffith@rcsi.ie
authors.forename: Darren M
authors.initials: DM
authors.lastname: Griffith
authors.forename: Brian
authors.initials: B
authors.lastname: Duff
authors.forename: Kyrill Y
authors.initials: KY
authors.lastname: Suponitsky
authors.forename: Kevin
authors.initials: K
authors.lastname: Kavanagh
authors.forename: Maria P
authors.initials: MP
authors.lastname: Morgan
authors.forename: Denise
authors.initials: D
authors.lastname: Egan
authors.forename: Celine J
authors.initials: CJ
authors.lastname: Marmion
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D009153:Mutagens / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D009153:Mutagens; D009944:Organoplatinum Compounds; D014635:Valproic Acid