|Ph.D||University of Illinois||1990|
|B.S.||University of Illinois||1985|
|B.A.||Ohio Wesleyan University||1984|
|NIH Postdoctoral Fellow,||University of South Carolina||1990-1993|
|Professor of Chemistry||Baylor University||1993-|
A primary focus of the research efforts of my group lies in the total synthesis of structurally challenging and biologically relevant and interesting natural products. Specifically, we have a special interest in the synthesis of anti-tumor, anti-mitotic agents (such as rhizoxin) which mediate their biological activity through an interaction with tubulin.
The development of a unified synthetic approach to compounds of this type accomplishes several goals: 1) It provides the opportunity to evaluate small portions of the total molecule (available only through synthesis) for their biochemical activity with tubulin. 2) It affords new insight into chemical transformations and serves to "test" and expand the tools of asymmetric synthesis. 3) A concise synthetic route to a natural product provides a means to modify the existing structure thereby preparing derivatives which may, in fact, be more biologically active than their "parent" natural product. 4) Total synthesis, in and of itself, often displays itself as a monumental accomplishment which reflects the history, versatility, collective knowledge, reasoning, and artistic accruement of the overall discipline of organic chemistry.
Molecular Probes for Tubulin
An important goal in the evaluation of potential chemotherapeutic agents continues to center on the establishment of mechanisms of action by which these compounds exert their biological effects. A detailed understanding of a particular biological mode of action is important not only for the efficient design of new, more potent drugs, but also to glean additional insight into the etiology of the given disease itself. A variety of clinically-promising compounds which demonstrate potent cytotoxic and antitumor activity are known to effect their primary mode of action through an efficient inhibition of tubulin polymerization. This class of compounds undergoes an initial binding interaction to the protein tubulin which in turn arrests the ability of tubulin to polymerize into microtubules which are essential components for cell maintenance and division. The development of both photosensitive and chemical (electrophilic) molecular probes for tubulin is therefore of significance in order to learn detailed information concerning the "chemical environment" of the "small molecule" binding domain of tubulin. Information of this nature is paramount for the design of new more potent inhibitors of tubulin polymerization and hence improved, more effective antitumor agents.
The ultimate success of a particular molecular probe is often synergistically linked to our ability to prepare the probe in radiolabeled form for detailed biochemical evaluation. We maintain an active interest in establishing new, facile, and general synthetic transformations which allow the incorporation of tritium and other radioisotopes in high specific activity into a given molecular framework.
We have an active and ongoing interest in learning as much as possible concerning small molecule-large molecule interactions such as those involved in a ligand binding to an enzyme or protein. Molecular modeling, including energy minimization, conformational analysis, docking characteristics, and molecular dynamics is an extremely useful technique for the systematic, theoretical evaluation of complex interactions of this nature. It is our intention that information gained from molecular modeling studies will suggest new ligands for synthesis and add to the overall collective knowledge of binding interactions.