Enhanced anti-cancer efficacy to cancer cells by a novel monofunctional mononuclear platinum( ii ) complex containing a mixed S,N,S-donor ligand

A novel mononuclear platinum( ii ) complex, [Pt L Cl]Cl ( 1 , where L = N -(4-(benzo[ d ]oxazol-2-yl)phenyl)-2-(bis(2-ethylthioethyl)amino)acetamide), was synthesized containing an S , N , S -donor monochloroplatinum( ii ) moiety tethered to a planar 2-(4-aminophenyl)benzoxazole unit by an amidic bond. [Pt L′ Cl]Cl ( 2 , where L′ = bis(2-ethylthioethyl)amine), the tridentate chelating Pt II motif of 1 , was also synthesized. Complex 1 exhibited a cytotoxicity comparable to that of cisplatin against MCF-7 cell lines and slightly higher activities against HeLa and A-549 cell lines. Compared to the activities of 2 , L , and L′ , the potent cytotoxicity of 1 should result from two aspects: the platinum moiety and the 2-(4-aminophenyl)benzoxazole unit. DNA binding experiments demonstrated that 1 could bind to DNA in a dual binding mode, i.e. , intercalation plus monofunctional platination, and 2-(4-aminophenyl)benzoxazole unit in 1 's structure should act as an intercalating group. Investigations of the reaction of 1 with 5′-GMP showed that 1 could coordinate with N7-GMP to form the Pt–GMP adduct. Thus, 1 has the potential to form monofunctional Pt–DNA adducts in vivo . Similarly, the glutathione (GSH) ligand could also be coordinated to the Pt( ii ) center to form a monodentate Pt–GS complex. However, the reaction towards GSH was indeed retarded by the bulky ligand of 1 , implying that the side-effects related to GSH might be reduced in vivo . The competition experiments of 1 with 5′-GMP and GSH showed that 1 reacted much faster with GSH than with 5′-GMP, but this did not prevent the formation of a certain amount of the Pt–GMP adduct.