Semisynthetic Maytansine Analogues for the Targeted Treatment of Cancer

J Med Chem. 2006 Jul 13;49(14):4392-408. doi: 10.1021/jm060319f.

Abstract

Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Disulfides / chemical synthesis
  • Disulfides / chemistry
  • Disulfides / pharmacology
  • Drug Carriers
  • Drug Delivery Systems
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Maytansine / analogs & derivatives*
  • Maytansine / chemical synthesis*
  • Maytansine / chemistry
  • Maytansine / pharmacology
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology
  • Transplantation, Heterologous

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Disulfides
  • Drug Carriers
  • Sulfhydryl Compounds
  • Maytansine