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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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 26, 2010
- 年：2010
- 卷：53
- 期：16
- 页码：6210-6227
- 全文大小：1267K
- 年卷期：v.53,no.16(August 26, 2010)
- ISSN：1520-4804
文摘
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.