Novel organotin complexes with phenol and imidazole moieties for optimized antitumor properties

Abstract

A series of novel imidazole-containing ligands and their organotin complexes were synthesized and characterized by NMR, IR, MALDI and elemental analysis. Redox behavior was studied by cyclic voltammetry (CV). Antioxidant properties were estimated in model reactions of single-electron reduction (CUPRAC-test), scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and O2−. radical anion, enzymatic oxidation of linoleic acid by lipoxygenase and Fe3+-induced lipid peroxidation of rat liver homogenates. It was found that ligands and complexes both possess radical scavenging activity of prolonged action type. Compounds exhibited notable antioxidant activity in lipid peroxidation. Cytotoxicity was estimated in standard MTT-test on multiple cell lines. Compounds demonstrated high toxicity on colon carcinoma and breast cancer cells and based on obtained data, lead compound was proposed. Additional assays were carried out for the lead compound, including regular MTT-test on cancer cells possessing various resistant mechanisms and modified MTT-test on tumor tissue samples, obtained from patients as well as apoptosis and cell cycle studies. All organotin complexes were also studied for their influence on tubulin polymerization. It was demonstrated that obtained compounds demonstrate unorthodox activity, promoting microtubules assembly rate instead of inhibiting it. Significant influence of compound 5 on G2/M phase of cell cycle is in accordance with influence on tubulin polymerization and lets us to mark synthesized compounds as mitotic poisons. The results open up the scopes for the search of novel antitumor agents for treatment of advanced forms of cancer.