通过体外毒性和分子建模对一系列二嗪桥联双核铂（II）配合物的合成与评估：铂（II）配合物的结构与活性之间的相关性

Synthesis and evaluation of series of diazine-bridged dinuclear platinum(II) complexes through in vitro toxicity and molecular modeling: correlation between structure and activity of Pt(II) complexes.

作者信息

Senerovic Lidija, Zivkovic Marija D, Veselinovic Aleksandar, Pavic Aleksandar, Djuran Milos I, Rajkovic Snezana, Nikodinovic-Runic Jasmina

机构信息

Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Vojvode Stepe 444a, 11000 Belgrade, Serbia.

出版信息

J Med Chem. 2015 Feb 12;58(3):1442-51. doi: 10.1021/jm5017686. Epub 2015 Jan 13.

DOI:10.1021/jm5017686

PMID:25551180

Abstract

Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(μ-pz)}(2+) (L, ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd) and one pyridazine (pydz) bridged {[Pt(en)Cl]2(μ-pydz)}(2+) complex were prepared. The anticancer potential of these complexes were determined through in vitro cytotoxicity assay in human fibroblasts (MRC5) and two carcinoma cell lines (A375 and HCT116), interaction with double stranded DNA through in vitro assay, and molecular docking study. All complexes inhibited cell proliferation with inhibitory concentrations in the 0.5-120 μM range. While {[Pt(1,3-pd)Cl]2(μ-pz)}(2+) showed improved activity and {[Pt(en)Cl]2(μ-pydz)}(2+) showed comparable activity to that of clinically relevant cisplatin, {[Pt(en)Cl]2(μ-pydz)}(2+) was less toxic in an assay with zebrafish (Danio rerio) embryos, causing no adverse developmental effects. The in vitro cytotoxicity of all diazine-bridged dinuclear Pt(II) complexes is discussed in correlation to their structural characteristics.

摘要

多核铂（II）配合物是一类具有潜在临床意义的新型有前景的抗癌剂。制备了一系列通式为{[Pt(L)Cl]2(μ-pz)}(2+)（L为乙二胺，en；(±)-1,2-丙二胺，1,2-pn；异丁二胺，ibn；反式-(±)-1,2-二氨基环己烷，dach；1,3-丙二胺，1,3-pd；2,2-二甲基-1,3-丙二胺，2,2-diMe-1,3-pd）的吡嗪（pz）桥连双核铂（II）配合物以及一个哒嗪（pydz）桥连的{[Pt(en)Cl]2(μ-pydz)}(2+)配合物。通过在人成纤维细胞（MRC5）和两种癌细胞系（A375和HCT116）中进行体外细胞毒性试验、体外试验研究与双链DNA的相互作用以及分子对接研究，确定了这些配合物的抗癌潜力。所有配合物均抑制细胞增殖，抑制浓度在0.5 - 120μM范围内。虽然{[Pt(1,3-pd)Cl]2(μ-pz)}(2+)表现出增强的活性，{[Pt(en)Cl]2(μ-pydz)}(2+)表现出与临床相关顺铂相当的活性，但在斑马鱼（Danio rerio）胚胎试验中，{[Pt(en)Cl]2(μ-pydz)}(2+)的毒性较小，未造成不良发育影响。讨论了所有二嗪桥连双核铂（II）配合物的体外细胞毒性与其结构特征的相关性。