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

• Published in: Journal of medicinal chemistry 2015-02, Vol.58 (3), p.1442-1451
• Main Authors: Senerovic, Lidija, Zivkovic, Marija D, Veselinovic, Aleksandar, Pavic, Aleksandar, Djuran, Milos I, Rajkovic, Snezana, Nikodinovic-Runic, Jasmina
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fibroblasts - drug effects; HCT116 Cells; Humans; Molecular Docking Simulation; Molecular Structure; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Platinum - chemistry; Structure-Activity Relationship; Zebrafish - embryology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5017686

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.