Design and synthesis of a fluoroindolocarbazole series as selective topoisomerase I active agents. Discovery of water-soluble 3,9-difluoro-12,13-dihydro-13-[6-amino-beta-D-glucopyranosyl]-5H,13H-benzo[b]- thienyl[2,3-a]pyrrolo[3,4-c]carbazole- 5,7(6H)-dione (BMS-251873) with curative antitumor activity against prostate carcinoma xenograft tumor model

J Med Chem. 2004 Mar 25;47(7):1609-12. doi: 10.1021/jm034197s.

Abstract

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Carbazoles / chemical synthesis*
  • Carbazoles / chemistry
  • Carbazoles / pharmacology
  • Glucosides / chemical synthesis*
  • Glucosides / chemistry
  • Glucosides / pharmacology
  • Male
  • Mice
  • Neoplasm Transplantation
  • Prostatic Neoplasms / drug therapy*
  • Solubility
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors*
  • Water
  • Xenograft Model Antitumor Assays

Substances

  • 3,9-difluoro-12,13-dihydro-13-(6-aminoglucopyranosyl)-5H,13H-benzo(b)thienyl(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6H)-dione
  • Antineoplastic Agents
  • Carbazoles
  • Glucosides
  • Topoisomerase I Inhibitors
  • Water