title: Cyclophosphamide (NSC-26271)-related phosphoramide mustards- recent advances and historical perspective.
abstract: The antitumor activity of three of the most phosphoramide mustards, NSC-69947, NSC-72505, and NSC-72510, was compared with that of phosphoramide mustard (NSC-69945), the apparent active metabolite of cyclophosphamide (CP), against the L1210, P388, B16, and Lewis lung tumor systems. This comparison did not reveal any significant differences in the patterns of inhibitory activity predictive of significant advantages in the clinic of any of these compounds over CP or NSC-69945. Attempts to prepare aldophosphamide, the key intermediate in CP metabolism, by oxidation of hydroxyphosphamide under the Sarett reaction conditions lead primarily to 4-ketocyclophosphamide. Under milder conditions the product isolated appears to be the elusive aldophosphamide on the basis of positive alkylating and aldehyde tests, Rf and infrared data, and the formation and characterization of a semicarbazone. The possibility that this product is an equilibrium mixture with the tautomeric 4-hydroxycyclophosphamide has not been as yet defintely ruled out. Sarett oxidation of homohydroxyphosphamide straightforwardly gives the stable analog, homoaldophosphamide. Biologic testing of this putative aldophosphamide in direct comparison with homoaldophosphamide, CP, and NSC-69945 reveals that aldophosphamide is a potent antitumor agent indistinguishable in activity from CP and NSC-69945, whereas homoaldophosphamide is inactive. These results provide confirmatory evidence for the postulated role of aldophosphamide as an intermediate in CP metabolism and suggest, furthermore, that aldophosphamide itself is not active in vivo, requiring transformation to NSC-69945 via beta-elimination of acrolein to exert its antitumor effects. An historical account of the development of the phosphoramide mustard field is also given.
mesh_terms: D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction
chemical_list: D009588:Nitrogen Mustard Compounds; D003520:Cyclophosphamide