Synthesis and study of a spin-labeled cyclophosphamide analog 3-(1-oxy-2,2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide

Abstract

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.

Platinum Complexes with Bioactive Nitroxyl Radicals: Synthesis and Antitumor Properties

“…Nitroxyl derivatives of (thio)phosphamides (Shapiro et al, 1971;Emanuel et al, 1976;Sosnovsky & Paul, 1984;Sosnovsky & Li, 1985a), cyclophosphamide (Tsui et al, 1982), actinomycin D (Sinha et al, 1979), ethylenimino triazines (Emanuel & Konovalova, 1992), nitrosoureas (Raikov et al, 1985;Sosnovsky & Li, 1985b;Emanuel et al, 1986;Sen', 1993), 5-fluorouracil (Emanuel et al, 1985;Sen' et al, 1989), daunorubicin (Emanuel et al, 1982) were synthesized and studied. In comparison with the parent compounds, nitroxyl derivatives of the cytostatic drugs possess lower overall toxicity in animal studies and higher values of the half inhibitory concentrations IC50 in cell cultures.…”