The relative alkylating activities of two of the cytotoxic metabolites of cyclophosphamide, phosphoramide mustard and nornitrogen mustard, have been studied at pH 4.6 and 7.4. The products formed on alkylation of ethanethiol by these metabolites have been identified, confirming that phosphoramide mustard undergoes alkylation reactions as an intact molecule. Deuterated analogs of the two metabolites have been synthesized, namely N,N-bis(2,2-dideutero-2-chloroethyl)-phosphorodiamidic acid and N,N-bis(2,2-dideutero-2-chloroethyl)amine, and used to determine that alkylation proceeds directly via an aziridinium intermediate rather than a direct SN2 displacement of the chlorine atom.

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This research was supported by USPHS, NIH Grants CA-16783 and GM-21248, and by Grants from the Andrew Mellon Fund and the American Cancer Society, Maryland Division. The synthesis of N,N-bis(2,2-dideutero-2-chloroethyl)phosphorodiamidic acid was reported at the Symposium on Metabolism and Mechanism of Action of Cyclophosphamide, London, U. K., July 10–12, 1975.

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©1976 American Association for Cancer Research.
1976
Cancer Research, Inc.