Synthesis and Biological Activity of Water-Soluble Maleimide Derivatives of the Anticancer Drug Carboplatin Designed as Albumin-Binding Prodrugs

Bioconjug Chem. Nov-Dec 2004;15(6):1349-59. doi: 10.1021/bc049829j.

Abstract

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / metabolism
  • Carboplatin / analogs & derivatives
  • Carboplatin / chemical synthesis*
  • Carboplatin / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Maleimides / chemical synthesis*
  • Maleimides / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Prodrugs / chemical synthesis*
  • Prodrugs / metabolism
  • Protein Binding / physiology
  • Serum Albumin / metabolism*
  • Solubility
  • Water / metabolism
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Maleimides
  • Prodrugs
  • Serum Albumin
  • Water
  • maleimide
  • Carboplatin