Synthesis and study of a spin-labeled cyclophosphamide analogue, 3-(1-oxy-2,2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide.
3-(1-Oxy-2,2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide (7) was isolated in 36% yield following H2O2-Na2WO4 oxidation of 3-(2,2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide (6), which was synthesized in three steps (25% yield) starting with 4-amino-2,2,6,6-tetramethylpiperidine. Binding of 7 to mouse liver microsomes was investigated by optical and electron spin resonance spectroscopy. Compared with the mouse liver microsomal metabolism of 1, separate incubations of 6 and an ca. 1:1 mixture of 1 and 6 gave approximately 90 and 60% less acrolein, respectively. A spin-labeled metabolite of 7, viz., N-(1-oxy-2,2,6,6-tetramethyl-4-piperidinyl)phosphoramide mustard (9), was synthesized and its intramolecular O-alkylation at pH 7.4, 37 degrees C, was studied by 31P NMR spectroscopy. Compounds 7 and 9 were inactive in screening tests against L1210 lymphoid leukemia in mice.
D000171:Acrolein / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D055598:Chemical Phenomena; D002621:Chemistry; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D013113:Spin Labels / Q000138:chemical synthesis*; D013997:Time Factors
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D013113:Spin Labels; D000171:Acrolein; C035806:3-(1-oxy-2,2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System