新型组蛋白去乙酰化酶抑制剂丙戊酸的顺铂配合物；合成、体外细胞毒性和致突变性。

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

机构信息

Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland.

出版信息

J Inorg Biochem. 2011 Jun;105(6):793-9. doi: 10.1016/j.jinorgbio.2011.03.001. Epub 2011 Mar 14.

DOI:10.1016/j.jinorgbio.2011.03.001

PMID:21497577

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.

摘要

本文报道了众所周知的抗癫痫药物和组蛋白去乙酰化酶抑制剂丙戊酸（VPA）的 Pt 配合物的首例实例。Pt(II) 氨（m）胺前体[trans-PtCl2(NH3)(py)]和[trans-PtCl2(py)2]与硝酸银反应，随后与丙戊酸钠反应，分别得到 trans-[Pt(VPA(-1H))2(NH3)(py)]和 trans-[Pt(VPA(-1H))2(py)2]。两个配合物中的丙戊酸配体通过羧基功能与 Pt(II)中心结合，并以单齿配位方式结合。描述了 trans-[Pt(VPA(-1H))2(NH3)(py)]的 X 射线晶体结构。trans-[PtCl2(py)2]和 trans-[PtCl2(NH3)(py)]中的二氯配体被丙戊酸配体（VPA(-1H)）取代，分别生成 trans-[Pt(VPA(-1H))2(py)2]和 trans-[Pt(VPA(-1H))2(NH3)(py)]，显著增强了对 A2780（亲本）和 A2780cisR（顺铂耐药）卵巢癌细胞的细胞毒性。还报道了 trans-[Pt(VPA(-1H))2(NH3)(py)]和 trans-[Pt(VPA(-1H))2(py)2]的致突变性，使用 Ames 试验进行了测定。