title: Effects of N-substitution on the activation mechanisms of 4-hydroxycyclophosphamide analogues.
abstract: The activation mechanisms of the N-substituted 4-hydroxycyclophosphamide analogues 4-hydroxyifosfamide (2b), 4-hydroxytrofosfamide (2c), and 3-methyl-4-hydroxycyclophosphamide (2d) were compared with that of the unsubstituted parent compound 2a. The reaction kinetics of cis-2b, -2c, and -2d are qualitatively similar to those of 2a in that they undergo ring opening to the respective aldophosphamide intermediates 3, which can reclose to the cis- or trans-4-hydroxy isomers or undergo base-catalyzed beta-elimination to generate the corresponding phosphoramide mustard products 4. In contrast to the general acid catalysis observed for ring opening of 2a and 2d, the N-(chloroethyl)-substituted analogues 2b and 2c undergo specific base-catalyzed ring opening. This mechanistic difference was also illustrated by the rapid reaction of 2a and 2d with sodium 2-mercaptoethanesulfonate (Mesna) under acidic conditions to give the 4-(alkylthio)-substituted cyclophosphamide derivatives 5a and 5d. Compounds 2b and 2c did not react with Mesna to generate 5b and 5c under these conditions. Both the fraction of aldehyde/hydrate present at equilibrium and the cytotoxicity against L1210 cells in vitro decreased in the order 2c greater than 2b greater than 2a greater than 2d. The plasma-catalyzed acceleration of phosphoramide mustard generation previously reported for 2a was also observed for these analogues.
authors.affiliation: Department of Pharmacology, University of Rochester, New York 14642.
authors.forename: C H
authors.initials: CH
authors.lastname: Kwon
authors.forename: R F
authors.initials: RF
authors.lastname: Borch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D009584:Nitrogen; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D009584:Nitrogen