The Chemistry of the Metabolites of Cyclophosphamide

Abstract

This is primarily an overview of the spontaneous (non-enzymatic l chemistry of the metabolites of cyclophosphamide, viz., cis- and trans-4- hydroxycyclophosphamide, aldophosphamide (and its hydrate), iminophosphamide. phosphoramide mustard, acrolein, and chloroethylaziridine. A brief description of detoxification products obtained through enzyme catalyzed reactions appears. Included as the historical basis for the development of cyclophosphamide is the chemistry of ni trog n mustards. Among the topics covered are: perturbations to metabolite distributions and half-lives effected by buffer, structure, pH and nucleophiles; effects of pH on mechanism; alkylation versus P-N bond hydrolysis; the influence of nucleophiles on alkylation product distributions; the influence of substituents on alkylation rates; and preactivated forms of cyclophosphamide as metabolite precursors (4-hydroperoxycyclophos­ phamide and mafosfamide). A review with 66 references.