Wayne K. Anderson

Dean, School of Pharmacy and Pharmaceutical Sciences
Professor of Chemistry

B.Sc. Pharmacy (University of Manitoba); M.Sc. Pharmaceutical Chemistry (University of Manitoba);
Ph.D. Medicinal Chemistry (University of Wisconsin at Madison)

Research Interests and Selected Recent P ublications

Drug design; prodrugs; natural product synthesis; new synthetic methods; heterocyclic chemistry.

The primary focus of the research in our laboratory is the design and synthesis of novel chemotherapeutic agents with potential utility in the treatment of cancer or AIDS. Three general approaches are used: (1) drug design based on novel "lead" structures; (2) design of enzyme inhibitors, and; (3) design of DNA targeted agents.

"Lead" structures are selected on the basis of distinctiveness, possible novel mechanism(s) of action, and/or potential for significant innovation. We use naturally occurring alkaloids, terpenes, marine toxins, and antibiotics as "lead" structures for drug design. We also use platinum diamine complexes, DNA cross-linking agents, and DNA minor groove binding agents as "lead" compounds. One challenge, once a "lead" structure is identified, is the development of specific structural hypotheses that can be tested in drug designs. We use computational chemistry, molecular modeling, and quantitative structure activity relationship correlations ("QSAR") as tools to develop and refine drug design hypotheses; X-ray crystallographic data and NMR data are often used in conjunction with these studies. The synthesis of the newly designed compounds is also a major challenge, and, often synthetic routes are designed to permit maximal structural divergence.

Several different projects are currently in progress.

• In the area of natural product synthesis, we recently developed a synthesis for halomon, a tumor inhibitory polyhalogenated marine toxin. We are currently investigating potential methods for enantioselective halogenations of achiral alkenes as part of our chemical studies with this novel new agent. No enantioselective methods are currently available for this purpose. Another focus of our natural product synthetic efforts is in the family of tyloindicine alkaloids.

• A major enzyme target in our laboratory is inosine monophosphate dehydrogenase. We are developing a computer model of the active site of this enzyme and are using that model to design inhibitors. Some of our inhibitor designs use mycophenolic acid as the "lead" compound. Inhibitors of this enzyme have antitumor, antiviral, immunosuppressive, or antiparasitic activity. The synthesis of our target compounds requires, in some instances, the development of new methods for the synthesis of heterocyclic compounds.

• Platinum complexes such as cisplatin are widely used to treat cancer. We have been involved in the design of new diamine ligands (e.g., beta- and gamma-aminosilanes) that impart different properties to the platinum complex and thereby influence factors such as drug distribution, sequence selectivity, and DNA repair (e.g., silaplatin).

• Our laboratory is also involved in the design and synthesis of novel bifunctional electrophiles where new approaches to latentiate chemical reactivity ("prodrugs") is one important focus. Some of our activities focus on a drug developed in our laboratory, carmethizole, as a "lead" structure for new drug development.

Inosine monophosphate dehydrogenase (IMPD) catalyzes the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) and is the rate limiting enzyme involved in the de novo biosynthesis of guanine nucleotides.

Wayne K. Anderson wka@buffalo.edu