Synthesis and biological activity of water-soluble maleimide derivatives of the anticancer drug carboplatin designed as albumin-binding prodrugs

Four platinum (II) complexes (13-16) were synthesized by reacting either [Pt trans-DACH](NO3)(2) with a 6-maleimidocaproic acid, a 15-maleimido-4,7,10,13-tetroxapentadecanoic acid, and a 6-maleimido-4-oxacaproic ester derivative of cyclobutane-1,1-dicarboxylic acid (CDBA) or [Pt(NH3)(2)](NO3)(2) with a 6-maleimido-4-oxacaproic ester derivative of CBDA. Both complexes containing the 6-maleimido4-oxacaproic ester (15, 16) showed good water solubility ( greater than or equal to8 mg/mL) and CE experiments revealed rapid binding to human serum albumin and the formation of biadducts with dGMP and dAMP. In the MaTu xenograft model in nude mice, both complexes showed an improved antitumor effect at their maximum tolerated dose (2 x 50 mg/kg carboplatin equivalents) compared to therapy with carboplatin at equimolar dose or at its optimal dose (2 x 75 mg/kg).