Acetonimine and 4-imino-2-methylpentan-2-amino platinum(II) complexes: synthesis and in vitro antitumor activity

The reaction of Pt(dmba)(PPh3)Cl] where dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl] with aqueous ammonia in acetone in the presence of AgClO4 gives the acetonimine complex Pt(dmba)(PPh3)(NH=CMe2)]ClO4 (1). The reaction of Pt(dmba)(DMSO)Cl] with aqueous ammonia in acetone in the presence of AgClO4 gives a mixture of Pt(dmba)(NH=CMe2)2]ClO4 (2) and Pt(dmba)(imam)]ClO4 (3a) (where imam = 4-imino-2-methylpentan-2-amino). Pt(dmba)(DMSO)Cl] reacts with Ag(NH=CMe2)2]ClO4 in a 1:1 molar ratio to give Pt(dmba)(DMSO)(NH=CMe2)]ClO4 (4). The reaction of Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone at 70 degrees C in the presence of KOH gives Pt(dmba)(CH2COMe)(NH=CMe2)] (5), whereas the reaction of Pt(dmba)(DMSO)Cl] with 20% aqueous ammonia in acetone in the absence of KOH gives Pt(dmba)(imam)]Cl (3b). The reaction of NBu4]2Pt2(C6F5)4(mu-Cl)2] with Ag(NH=CMe2)2]ClO4 in a 1:2 molar ratio produces cis-Pt(C6F5)2(NH=CMe2)2] (6). The crystal structures of 1 x 2 Me2CO, 2, 3a, 5, and 6 have been determined. Values of IC50 were calculated for the new platinum complexes against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR) and breast cancers (T47D). At 48 h incubation time complexes 1, 4, and 5 show very low resistance factors against an A2780 cell line which has acquired resistance to cisplatin. 1, 4, and 5 were more active than cisplatin in T47D (up to 30-fold in some cases). The DNA adduct formation of 1, 4, and 5 was followed by circular dichroism and electrophoretic mobility.