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.

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.

• Authors: Balu N Balasubramanian, Denis R St Laurent, Mark G Saulnier, Byron H Long, Carol Bachand, Francis Beaulieu, Wendy Clarke, Milind Deshpande, Jeffrey Eummer, Craig R Fairchild, David B Frennesson, Robert Kramer, Frank Y Lee, Mikael Mahler, Alain Martel, B Narasimhulu Naidu, William C Rose, John Russell, Edward Ruediger, Carola Solomon, Karen M Stoffan, Henry Wong, John J Wright, Kurt Zimmermann, Dolatrai M Vyas
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 7 Pg. 1609-12 (Mar 25 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15027851 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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