Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene.

Abstract

Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic hormone-refractory prostate cancer who failed prior treatment with two different standard chemotherapeutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement with a variety of nucleophiles to produce analogues that retain key functional groups required for biological activity including the reactive cyclopropylmethyl carbinol and alpha,beta-unsaturated ketone. As described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key functional groups and display potent biological activity toward target solid tumor cells in vitro but are relatively nontoxic toward a nontarget B-cell derived cell line.

• Authors: Trevor C McMorris, Ramesh Chimmani, Kashinatham Alisala, Michael D Staake, Gangadasu Banda, Michael J Kelner
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 3 Pg. 1109-16 (Feb 11 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20067264 (Publication Type: Journal Article)

Chemical References

• Carbamates
• Sesquiterpenes
• Spiro Compounds
• Sulfonamides
• acylfulvene
• Urea

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• B-Lymphocytes (drug effects)
• Carbamates (chemistry)
• Cell Line
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Sesquiterpenes (chemical synthesis, chemistry, pharmacology)
• Spiro Compounds (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Sulfonamides (chemistry)
• Urea (chemistry)