Mechanistic insights into toxic effects of a benzotriazolate-bridged dinuclear platinum(II) compound in tumor cells

Abstract We examined toxicity in tumor cells as well as some early phases of the mechanism underlying biological properties of benzotriazolate (Btaz)-bridged dinuclear Pt II complex ([{ cis -Pt(NH 3 ) 2 Cl} 2 (μ-Btaz-H)]Cl ( 1 )). This dinuclear bifunctional Pt II complex utilizes rigid aromatic ring of azole as a linker between two Pt atoms, featuring at the same time non-bridging chloride ions as leaving groups. The results of the present work demonstrate that the toxicity of 1 in several human tumor cell lines was lower than that of conventional cisplatin. The results obtained are consistent with the idea, and support the postulate that deactivation of 1 by sulfur-containing compounds is a significant factor contributing to reduced DNA binding of 1 in cells and subsequently to its reduced cytotoxicity. In addition, the observations that DNA adducts of 1 and cisplatin distort DNA conformation differently and that monofunctional DNA adducts of 1 are converted to more toxic bifunctional cross-links considerably more slowly in comparison with cisplatin may contribute to the reduced cytoxicity of 1 . The results of the present work afford further details on the mechanism underlying biological effects of bifunctional polynuclear Pt II compounds and should provide a more rational basis for the design of new antitumor metallodrugs and chemotherapeutic strategies.