The objectives of this proposal are to synthesize and biologically evaluate a series of analogs of aldophosphamide, one of the major primary metabolites of cyclophosphamide. The analogs are designed to elucidate the structural correlates of antitumor activity for this general class of compounds, particularly the contribution of intermediate '4-hydroxy' cyclic structures to drug selectivity. A further major goal is to extend these key structural features to other cytotoxic agents in an attempt to enhance their therapeutic efficacy.
The specific aims are: 1) to synthesize a series of analog prodrugs of aldophosphamide, 2) to determine their physicochemical properties, 3) to investigate their cytotoxicities, in vitro, against L1210 murine leukemia cells, 4) to determine their antitumor activities in mice bearing L1210 leukemia, 5) to study their biotransformation by carboxylate esterases, by mouse plasma, and by intact mice, 6) to synthesize and biologically evaluate an analog of 5-fluoro-2'-deoxyuridine 5'-monophosphate that incorporates structural features that may contribute to the selectivity of the aldophosphamide analogs.
