Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene.
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.
McMorris
Trevor C
TC
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0358, USA.
Chimmani
Ramesh
R
Alisala
Kashinatham
K
Staake
Michael D
MD
Banda
Gangadasu
G
Kelner
Michael J
MJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects*; D002219:Carbamates / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D014508:Urea / Q000737:chemistry*
D002219:Carbamates; D012717:Sesquiterpenes; D013141:Spiro Compounds; D013449:Sulfonamides; C079422:acylfulvene; D014508:Urea