Carboplatin derivatives with superior antitumor activity compared to the parent compound

A series of new carboplatin derivatives was synthesized by introducing fluoro, chloro, bromo and hydroxy substituents into the cyclobutane ring. The carboxylic acid groups were used for the complexation with platinum(II) fragments bearing two ammonia and (RR/SS)-trans-1,2-diaminocyclohexane ligands, respectively, as non-leaving groups. The antiproliferative activity of the new carboplatin analogues differing in the cyclobutanedicarboxylate ligands and the type of platinum fragment were studied in tests with J82 bladder cancer cells and SK-OV-3 as well as cisplatin-resistant NIH:OVCAR-3 ovarian cancer cells. The most active compounds were the 3-fluoro, 3-chloro and 3,3-difluoro derivatives of carboplatin. NMR spectroscopy showed that cis-diammine(3-chloro-1,1-cyclobutanedicarboxylato)platinum(II) was hydrolyzed much faster than carboplatin explaining its higher cytostatic activity.