56922-83-9Relevant articles and documents
NMR Spectroscopic Studies of Intermediary Metabolites of Cyclophosphamide. A Comprehensive Kinetic Analysis of the Interconversion of cis- and trans-4-Hydroxycyclophosphamide with Aldophosphamide and the Concomitant Partitioning of Aldophosphamide between Irreversible Fragmentation ...
Zon, Gerald,Ludeman, Susan Marie,Brandt, Joan A.,Boyd, Victoria L.,Oezkan, Gunay,et al.
, p. 466 - 485 (1984)
Multinuclear (31P, 13C, 2H, and 1H) Fourier-transform NMR spectroscopy, with and without isotopically enriched materials, was used to identify and quantify, as a function of time, the following intermediary (short-lived) metabolites of the anticancer prodrug cyclophosphamide (1, Scheme I): cis-4-hydroxycyclophosphamide (cis-2), its trans isomer (trans-2), aldophosphamide (3), and its aldehyde-hydrate (5).Under a standard set of reaction conditions (1 M 2,6-dimethylpyridine buffer, pH 7.4, 37 deg C), the stereospecific deoxygenation of synthetic cis-4-hydroperoxycyclophosphamide (cis-12, 20 mM) with 4 equiv of sodium thiosulfate (Na2S2O3) afforded, after ca.20 min, a "pseudoequilibrium" distribution of cis-2, 3, 5, and trans-2, i.e., the relative proportions of these reactants (57:4:9:30, respectively) remained constant during their continual disappearance.NMR absorption signals indicative of "iminophosphamide" (8) and enol 6 were not detected ( "3" trans-2, as well as the rate constant (k3) for the irreversible fragmentation of 3.The values of k3 at pH 6.3, 7.4, and 7.8 were equal to 0.030 +/- 0.004, 0.090 +/- 0.008, and 0.169 +/- 0.006 min-1, respectively.Replacement of the HC(O)CH2 moiety in 3 with HC(O)CD2 led to a primary kinetic isotope effect (kH/kD = 5.6 +/- 0.4) for k3.The apparent half-lives (τ*1/2) for cis-2, "3", and trans-2 under the standard reaction conditions, at "pseudoequilibrium" (constant ratio of cis-2/"3"/trans-2), were each equal to ca.38 min, which is considerably shorter than the widely cited colorimetrically derived half-lives reported by earlier investigators.The values of τ*1/2 for cis-2, "3", and trans-2 were affected by pH in the same manner as that found for k3 but were relatively insensitive to the presence of either K(+), Na(+), Ca(2+), or Mg(2+).The presence of certain primary amines led to marked decreases in τ*1/2 and, in some cases, the formation of acyclic adducts of aldehyde 3.The relatively stable adduct formed from 3 and tris(hydroxymethyl)aminomethane (Tris) at pH 7.4 and 37 deg C gave rise to a 31P NMR signal that other investigators have mistakenly ascribed to 2. 31P NMR spectroscopy was also used to examine, in considerable detail, the manifold effects of N-acetyl-L-cysteine upon the chemistry of 2, "3", and 4, which featured the formation of a mixture of diastereomeric, acyclic ...
The Mechanism of Activation of 4-Hydroxycyclophosphamide
Borch, Richard F.,Millard, Jo Ann
, p. 427 - 431 (2007/10/02)
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 opennig of 4-hydroxycyclophosphamide to produce aldophosphamide (4).The ring-opennig 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 β-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 ca. 5 provides a convenient method to prepare a stable equilibrium mixture of activated cyclophosphamide metabolites suitable for in vitro use.
A new oxidized derivative of cyclophosphamide obtained from ozonolysis of O-3-butenyl N,N-bis(2-chloroethyl)phosphorodiamidate
Van Der Steen,Westra,Benckhuysen,Schulten
, p. 5691 - 5692 (2007/10/02)
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