Objective: The objective of the proposed research is to exploit our previous discovery of the potent experimental antitumor agent isophosphoramide mustard (IPM). This metabolite of the clinically-effective ifosfamide (IFA), which is the ultimate alkylating form of IFA, displayed activity comparable to both IFA and cyclophosphamide (CPA), currently the most widely-used clinical anticancer drug of the alkylating agent class, against a spectrum of experimental leukemias and solid tumors; in addition, IPM retained its activity against CPA- and IFA-resistant L1210 and P388 leukemias (Struck et al., Brit. J. Cancer, in press) Synthesis of congeners of IPM with altered leaving groups is proposed in order to permit a structure-activity investigation for optimization of antitumor activity for this type of agent. Synthesis will involve replacement of chlorine of the phenyl ester of phosphorodichloridic acid with primary or secondary amines substituted in the beta or gamma position with chlorine, methanesulfonyloxy, or imidazolyl-sulfonyloxy groups. Congeners will be evaluated against L1210 leukemia in mice. Agents found to be comparable or superior to IPM against this tumor will be evaluated against the solid mouse tumors, Lewis lung carcinoma and mammary adenocarcinoma 16C. Congeners with activity superior to IPM against these 3 tumors will be evaluated further against B16 melanoma, ovarian sarcoma M5076, and colon tumor 38.
