The objectives of this proposal are to elucidate three-dimensional structures of a number of types of drugs that exhibit clinical utility or laboratory demonstrated potential as cancer chemotherapy agents. The long term goals are to identify specific molecular stereochemical features that are responsible for the agents' pharmacological activity, toxicity and selectivity of action. Once identified these stereochemical parameters may be individually modified in hopes of creating new drugs with greater potency and selectivity than those currently available. Categories of compounds to be investigated include substrates and inhibitors of the enzymes dihydrofolate reductase and thymidylate synthetase, cyclophosphamide derivatives, small peptides derived from the cellular basement membrane proteins fibronectin and laminin, organic chelates of rhenium and technetium, antiestrogens and organic dyes.
