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](NO(3))(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(NH(3))(2)](NO(3))(2) with a 6-maleimido-4-oxacaproic ester derivative of CBDA. Both complexes containing the 6-maleimido-4-oxacaproic ester (15, 16) showed good water solubility (>/=8 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).
Warnecke
André
A
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany, Max-Delbrück Centrum, Robert-Rössle-Strasse 10, 13122 Berlin, Germany.
Fichtner
Iduna
I
Garmann
Dirk
D
Jaehde
Ulrich
U
Kratz
Felix
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism; D016190:Carboplatin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D012709:Serum Albumin / Q000378:metabolism*; D012995:Solubility; D014867:Water / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D008301:Maleimides; D011355:Prodrugs; D012709:Serum Albumin; D014867:Water; C043592:maleimide; D016190:Carboplatin