Pyrrolo[2,1-c][1,4]benzodiazepine-beta-glucuronide prodrugs with a potential for selective therapy of solid tumors by PMT and ADEPT strategies

Bioorg Med Chem Lett. 2008 Jul 1;18(13):3769-73. doi: 10.1016/j.bmcl.2008.05.038. Epub 2008 May 16.

Abstract

Pyrrolo[2,1-c][1,4]benzodiazepine-beta-glucuronide prodrugs 15a-b, with a potential for selective therapy of solid tumors by PMT and ADEPT have been designed, synthesized and evaluated for selective cytotoxicity in the presence of the enzyme beta-glucuronidase. The prodrugs have been found to possess reduced cytotoxicity compared to the parent moieties, and are excellent substrates for the enzyme, exhibiting cytotoxicity selectively in the presence of the enzyme. Enhanced water solubility and improved stability are the other important outcomes upon modifying these molecules as their prodrugs.

MeSH terms

  • Alkylating Agents / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Benzodiazepinones / chemistry*
  • Chorionic Gonadotropin / chemistry
  • Glucuronides / chemistry*
  • Glucuronides / pharmacology
  • Humans
  • Kinetics
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Prodrugs / chemistry*
  • Solubility
  • Water / chemistry
  • gamma-Glutamyl Hydrolase / chemistry

Substances

  • Alkylating Agents
  • Antineoplastic Agents
  • Benzodiazepinones
  • Chorionic Gonadotropin
  • Glucuronides
  • Prodrugs
  • Water
  • gamma-Glutamyl Hydrolase