title: Chemically stable N-methyl-4-(alkylthio)cyclophosphamide derivatives as prodrugs of 4-hydroxycyclophosphamide.
abstract: Two prototype N-methyl-4-thio-substituted cyclophosphamide (CP) derivatives (5 and 6), prodrugs of 4-hydroxycyclophosphamide (4-HO-CP), were designed to undergo oxidative N-demethylation to release the active alkylating agent. These prodrugs were chemically stable until oxidatively N-demethylated in the presence of hepatic microsomal P-450 enzymes. While the metabolism of 5 was enhanced in the presence of phenobarbital-induced microsomes, 6 was unaffected. Compound 6 was more active than 5 against L1210 leukemia cells grown in mice and exhibited statistically significant activity against the small cell lung cancer panel in the National Cancer Institute anticancer drug screen. Compound 5, like CP (1), was inactive in this screen. Thus, placement of a dithioester at the 4-position of N-methyl-HO-CP as in 6 markedly changes its spectrum of activity and has resulted in a new type of CP-based prodrug with antitumor activity against small cell lung cancer as well as leukemia cells in vitro as shown by their ability to inhibit tumor cell growth at concentrations as low as 10(-6) M.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439.
authors.forename: K Y
authors.initials: KY
authors.lastname: Moon
authors.forename: F N
authors.initials: FN
authors.lastname: Shirota
authors.forename: N
authors.initials: N
authors.lastname: Baturay
authors.forename: C H
authors.initials: CH
authors.lastname: Kwon
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C092356:N(3)-methyl-4-(diethyldithiocarbamoyl)cyclophosphamide; C092355:N(3)-methyl-4-(propylthio)cyclophosphamide; D011355:Prodrugs; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide