Studies on cyclophosphamide metabolites and their related compounds. 2. Preparation of an active species of cyclophosphamide and related compounds

A synthetic study was made on the active metabolite of cyclophosphamide. Ozonolysis of O-(3 butenyl)-N,N-bis(2-chloroethyl)phosphorodiamidate, prepared by reaction of POC13 with 3-buten-1-ol followed by treatment with N,N-bis(2-chloroethyl)amine (nor mustard) and NH3, afforded 2-[bis(2-chloroethyl)a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1975-04, Vol.18 (4), p.376
Main Authors: Takamizawa, A, Matsumoto, S, Iwata, T, Tochino, Y, Katagiri, K, Yamaguchi, K
Format: Article
Language:English
Subjects:
Acetals - chemical synthesis
Acetals - therapeutic use
Animals
Body Weight
Cyclophosphamide - analogs & derivatives
Cyclophosphamide - chemical synthesis
Cyclophosphamide - therapeutic use
HeLa Cells
Lethal Dose 50
Leukemia L1210 - drug therapy
Magnetic Resonance Spectroscopy
Mechlorethamine - analogs & derivatives
Mechlorethamine - pharmacology
Mice
Mice, Inbred Strains
Peroxides - chemical synthesis
Peroxides - therapeutic use
Rats
Sarcoma, Yoshida - drug therapy
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Summary:A synthetic study was made on the active metabolite of cyclophosphamide. Ozonolysis of O-(3 butenyl)-N,N-bis(2-chloroethyl)phosphorodiamidate, prepared by reaction of POC13 with 3-buten-1-ol followed by treatment with N,N-bis(2-chloroethyl)amine (nor mustard) and NH3, afforded 2-[bis(2-chloroethyl)amino]-4-hydroperoxytetrahydro-2H-1, 3,2-oxazaphosphorine 2-oxide (4-hydroperoxycyclophosphamide). Deoxygenation of 4-hydroperoxycyclophosphamide by triphenylphosphine yielded 4-hydroxycyclophosphamide in a pure crystalline state. These products exhibited high cytostatic activity in both in vitro and in vivo experiments. The results give confirmatory evidence for the hypothesis that C4-hydroxylation on the 1,3,2-oxazaphosphorinane ring of cyclophosphamide is necessary for its activation.
ISSN:0022-2623
DOI:10.1021/jm00238a011