We are interested in the study of small molecules, of both synthetic and natural origin, as molecular probes to study protein function as a basis for drug design.

We are currently synthesizing a new series of conformationally restrained analogues of epothilone, a group of anticancer natural products with a mechanism of action similar to that of paclitaxel. Structure-activity studies of studies of epothilone have led to the synthesis of many new epothilone analogues, some of which have better parmacologic profiles than the natural epothilones. We have desigend and are in the process of synthesizing a new class of conformationally-restrained analogues of epothilone for structure-activity studies as well as for developing analogues more potent than the natural epothilones.

We are also investigating a new class of inhibitors of the human immunodeficiency virus-1 reverse transcriptase. These synthetic analogues, obtained by systematic and structure-activity based rational optimization of a natural product, inhibit the wild type as well as a double mutant form of HIV-1 reverse transcriptase, insensitive to other noncompetitive inhibitors. Of special interest is a sub-class of these agents that inhibits the strand transfer process during reverse transcription. Such inhibitors have potential as therapeutic agents expected to reduce the rate of recombination-associated mutations, a major cause of induced drug resistance in HIV-1.