Kwon C H, Borch R F
Department of Pharmacology, University of Rochester, New York 14642.
J Med Chem. 1989 Jul;32(7):1491-6. doi: 10.1021/jm00127a016.
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.
将N-取代的4-羟基环磷酰胺类似物4-羟基异环磷酰胺（2b）、4-羟基曲磷胺（2c）和3-甲基-4-羟基环磷酰胺（2d）的活化机制与未取代的母体化合物2a进行了比较。顺式-2b、-2c和-2d的反应动力学在定性上与2a相似，即它们会开环生成各自的醛磷酰胺中间体3，中间体3可以重新闭环形成顺式或反式4-羟基异构体，或者进行碱催化的β-消除反应生成相应的磷酰胺氮芥产物4。与2a和2d开环时观察到的一般酸催化不同，N-（氯乙基）取代的类似物2b和2c进行特定的碱催化开环。2a和2d在酸性条件下与2-巯基乙磺酸钠（美司钠）快速反应生成4-（烷硫基）取代的环磷酰胺衍生物5a和5d，这也说明了这种机理上的差异。在这些条件下，化合物2b和2c不与美司钠反应生成5b和5c。平衡时存在的醛/水合物比例以及对L1210细胞的体外细胞毒性均按2c＞2b＞2a＞2d的顺序降低。之前报道的2a血浆催化的磷酰胺氮芥生成加速现象在这些类似物中也观察到了。
