Synthesis of reactive metabolite-analogues of cyclophosphamide for comparisons of NMR kinetic parameters and anticancer screening data.
Ozonolysis of compounds with the general structure CH2 = CHR1CHR2CH2OP(O) (NHR3)NR42 gave, in each case, one major product which was an analogue of the cyclophosphamide (CP) metabolites aldophosphamide (AP) or 4-hydroxy-CP. 31P NMR spectra recorded for each of these compounds in aqueous buffered solutions at pH 7.4, 37 degrees C, revealed a cascade of reactions similar to those observed for AP and/or 4-hydroxy-CP, although the individual rate constants for these reactions were substituent-dependent. Aryl ketone analogues of AP did not give rise to detectable amounts of their cyclic hemiaminals, but those which produced phosphoramide mustards at rates similar to that found for AP were active against L1210 lymphoid leukaemia in mice. The results indicated that oncostatic selectivity may not require cell-specific oxidative detoxification.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice
D000970:Antineoplastic Agents; D003520:Cyclophosphamide