The mechanism of activation of 4-hydroxycyclophosphamide.
4-Hydroxycyclophosphamide (2/3) of unknown stereochemistry is the initial metabolite formed after administration of cyclophosphamide (1). Ultimate conversion to the cytotoxic metabolite phosphoramide mustard (6) is initiated by ring opening of 4-hydroxycyclophosphamide to produce aldophosphamide (4). The ring-opening reaction and subsequent equilibration of 2-4 are subject to general-acid catalysis, and the equilibrium composition is independent of buffer structure and pH. In contrast, formation of 6 from 4 proceeds by general-base-catalyzed beta-elimination. trans-4-Hydroxycyclophosphamide undergoes ring opening ca. 4 times faster than the cis isomer, and cyclization of 4 favors the trans isomer by a factor of ca. 3 over the cis isomer. The rapid equilibration of 2-5 and the absence of elimination to give 6 at pH approximately 5 provides a convenient method to prepare a stable equilibrium mixture of activated cyclophosphamide metabolites suitable for in vitro use.
D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods
C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide