The major objectives of this research are to determine the chemical mechanism of cyclophosphamide activation and its role in the drug's oncotoxic specificity, and to design and synthesize new cyclophosphamide analogs whose specificity is based upon mechanisms of activation. The primary focus will be on th mechanisms of conversion of 4 hydroxycyclophosphamide to the activated alkylating agent phosphoramide mustard via aldophosphamide and to reversibly deactivated products formed by exchange reaction at the 4 position.
The specific aims of these studies include an understanding of 1) the factors which affect substitution at the 4-position of activated cyclophosphamide derivatives; 2) the role of bifunctional catalysis in the activation of 4-hydroxycyclophosphamide; 3) the significance of the interconversions of activated metabolites with respect to drug activation and transport; and 4) the synthesis of analogs which are designed to reduce bladder toxicity, bypass hepatic activation, or utilize the cyclophosphamide activation pathway to deliver other phosphorylated compounds of therapeutic interest. Nuclear magnetic resonance (NMR) spectrometry, both proton and phosphorus, will be the primary tool for elucidating these mechanisms. Delineation of the activation mechanisms will be of immense importance by increasing our understanding of the factors which affect cyclophosphamide activation, dactivation, and toxicity, and by providing a chemica rationale for the design and synthesis of agents with improved oncotoxic specificity and fewer side effects.
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