title: 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.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0358, USA.
authors.forename: Trevor C
authors.initials: TC
authors.lastname: McMorris
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chimmani
authors.forename: Kashinatham
authors.initials: K
authors.lastname: Alisala
authors.forename: Michael D
authors.initials: MD
authors.lastname: Staake
authors.forename: Gangadasu
authors.initials: G
authors.lastname: Banda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelner
mesh_terms: 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*
chemical_list: D002219:Carbamates; D012717:Sesquiterpenes; D013141:Spiro Compounds; D013449:Sulfonamides; C079422:acylfulvene; D014508:Urea