ABSTRACT
Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven.
Subject(s)
Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/therapeutic use , Hydroxyurea/analogs & derivatives , Hydroxyurea/therapeutic use , Neoplasms/drug therapy , Sesquiterpenes/chemistry , Sesquiterpenes/therapeutic use , Acetylation , Agaricales/chemistry , Animals , Antineoplastic Agents, Alkylating/pharmacology , Cell Line, Tumor , Humans , Hydroxyurea/pharmacology , Mice, Inbred BALB C , Neoplasms/pathology , Polycyclic Sesquiterpenes , Sesquiterpenes/pharmacologyABSTRACT
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.
Subject(s)
Adenocarcinoma/pathology , B-Lymphocytes/drug effects , Carbamates/chemistry , Lung Neoplasms/pathology , Sulfonamides/chemistry , Urea/chemistry , Adenocarcinoma/drug therapy , Animals , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Lung Neoplasms/drug therapy , Mice , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Acylfulvenes, a class of semisynthetic analogs of Illudin S, show high toxicity toward prostate cancer cells. Here we probe the effect of changes in hydrophilic character of the analogs.
Subject(s)
Amines/chemistry , Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/toxicity , Sesquiterpenes/chemical synthesis , Sesquiterpenes/toxicity , Adenocarcinoma/pathology , Antineoplastic Agents, Alkylating/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Sesquiterpenes/chemistry , Structure-Activity RelationshipABSTRACT
Stereoselective synthesis of (-)-irofulven has been achieved by cycloaddition of (R)-5-chloro-5-methyl-2-cyclopentenone to the 1,3-dipolar intermediate from 1-acetyl-1-(diazoacetyl)cyclopropane. The enantiomer, (+)-irofulven, was prepared in a similar way starting with (S)-5-chloro-5-methyl-2-cyclopentenone. (+)-Irofulven was 5 to 6 times less toxic than (-)-irofulven to adenocarcinoma (MV 522) cells.
Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Acylation , Adenocarcinoma/drug therapy , Animals , Antineoplastic Agents, Alkylating/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Mice , Molecular Structure , Sesquiterpenes/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Reduction of (+/-)-5-chloro-5-methyl-2-cyclopentenone with BH(3).THF and catalytic (R)-2-methyl-CBS-oxazaborolidine gave readily separable diastereomers with high ee values. Oxidation of the diastereomers furnished the enantiomers of the chloromethylcyclopentenone.