title: Studies on cyclophosphamide metabolites and their related compounds. 2. Preparation of an active species of cyclophosphamide and related compounds.
abstract: 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.
mesh_terms: D000080:Acetals / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D006367:HeLa Cells; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008466:Mechlorethamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010545:Peroxides / Q000138:chemical synthesis / Q000627:therapeutic use; D051381:Rats; D012517:Sarcoma, Yoshida / Q000188:drug therapy
chemical_list: D000080:Acetals; D010545:Peroxides; D008466:Mechlorethamine; D003520:Cyclophosphamide