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

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-DM E 500)). The biological activity was strongly influenced by the cycloaliphatic amine ring size, with trans-[Pt(NH2CH(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.