Synthesis and antitumor activity of ammine/amine platinum(II) and (IV) complexes

Dimeric platinum complexes, [Pt(RNH2)I2]2 (where R = H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), have been synthesized by reactions of diiodoplatinum compounds with perchloric acid in water/ethanol solutions. The dimerization varies from several hours to a few days depending upon the length of the carbon chain in the alkylamines and the process can be conveniently monitored by 195Pt NMR spectroscopy. All these dimers exhibit two closely separated resonances around -4000 ppm (vs K2PtCl4 at -1620 ppm) in dimethylformamide. Reactions of [Pt(NH3)I2]2 with alkylamines do not yield the desired mixed ammine/amine complexes, which are obtained subsequently by treatment of the alkylamine dimer [Pt(RNH2)I2]2 with ammonium hydroxide in water. By using this latter procedure, a novel class of ammine/amine platinum complexes of the type PtII(NH3)(RNH2)Cl2, PtIV(NH3)(RNH2)X2A2, and PtIV(NH3)(RNH2)(CBDCA)A2.H2O, where X2 = chloro or 1,1-cyclobutanedicarboxylato (CBDCA), A = OH, Cl, or OCOCH3, have been synthesized and characterized by elemental analysis, infrared, and 195Pt NMR spectroscopic techniques. The alicyclic ammine/amine Pt(II) complexes, where R is C3-C6 were selected as representative of the class to undergo antitumor evaluations. The compounds had excellent activity against murine leukemic L1210/0 cells with cyclobutylamine-, cyclopentylamine- and cyclohexylamine-containing complexes demonstrating cytotoxicity superior to that of the clinically established cisplatin.