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

• Published in: Journal of medicinal chemistry 2010-08, Vol.53 (16), p.6210-6227
• Main Authors: Marzano, Cristina, Mazzega Sbovata, Silvia, Gandin, Valentina, Colavito, Davide, Del Giudice, Elda, Michelin, Rino A, Venzo, Alfonso, Seraglia, Roberta, Benetollo, Franco, Schiavon, Mariano, Bertani, Roberta
• Format: Article
• Language: English
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Lewis Lung - drug therapy; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystallography, X-Ray; DNA Damage - drug effects; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred BALB C; Platinum; Solubility; Stereoisomerism; Structure-Activity Relationship; Tumor Suppressor Protein p53 - biosynthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1006534

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(NH2 CH(CH2)4 CH2)2{N(H)C(CH3)N(H)CH(CH2)4 CH2}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.