Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy

Eur J Med Chem. 2013 Sep:67:75-80. doi: 10.1016/j.ejmech.2013.06.037. Epub 2013 Jun 25.

Abstract

We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is significantly less toxic than the parent drug. However, in the presence of β-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.

Keywords: Cancer; Chemotherapy; Glucuronide; Prodrug; Tumor targeting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Lewis Lung / drug therapy*
  • Carcinoma, Lewis Lung / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Glucuronides / chemical synthesis
  • Glucuronides / chemistry
  • Glucuronides / pharmacology*
  • Humans
  • KB Cells
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Glucuronides
  • Oligopeptides
  • Prodrugs
  • monomethyl auristatin E