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A New Class of Antitumor trans-Amine-Amidine-Pt(II) Cationic Complexes: Influence of Chemical Structure and Solvent on in Vitro and in Vivo Tumor Cell Proliferation

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journal contribution
posted on 26.08.2010, 00:00 by Cristina Marzano, Silvia Mazzega Sbovata, Valentina Gandin, Davide Colavito, Elda Del Giudice, Rino A. Michelin, Alfonso Venzo, Roberta Seraglia, Franco Benetollo, Mariano Schiavon, Roberta Bertani
The reactions of cyclopropylamine, cyclopentylamine, and cyclohexylamine with trans-[PtCl2(NCMe)2] afforded the bis-cationic complexes trans-[Pt(amine)2(Z-amidine)2]2+[Cl]2, 1−3. The solution behavior and biological activity have been studied in different solvents (DMSO, water, polyethylene glycol (PEG 400), and polyethylene glycol dimethyl ether (PEG-DME 500)). The biological activity was strongly influenced by the cycloaliphatic amine ring size, with trans-[Pt(NH2CH(CH2)4CH2)2{N(H)C(CH3)N(H)CH(CH2)4CH2}2]2+[Cl]2 (3) being the most active compound. Complex 3 overcame both cisplatin and MDR resistance, inducing cancer cell death through p53-mediated apoptosis. Alkaline single-cell gel electrophoresis experiments indicated direct DNA damage, reasonably attributable to DNA adducts of trans-[PtCl(amine)(Z-amidine)2][Cl] species, which can evolve to produce disruptive and nonrepairable lesions on DNA, thus leading to the drug-induced programmed cancer cell death. Preliminary in vivo antitumor studies on C57BL mice bearing Lewis lung carcinoma highlighted that complex 3 promoted a significant and dose-dependent tumor growth inhibition without adverse side effects.