CURRENT RESEARCH AREAS

1. Chemistry and Biology of Natural Products with Medicinal Promise

Our efforts in this area are aimed at:

(a) Development of practical chemical syntheses of natural products.

(b) Construction of libraries of analogues followed by their biological evaluation. The goal is to derive structure-activity relationships and identify analogues, which may have improved activity and reduced toxicity profiles.

(c) Preparation of affinity probes for the elucidation of biological modes of action.

For example, a total synthesis of (+)- and (-)-cyclophellitol, a promising anti-HIV agent, from D-xylose has been accomplished through utilization of the latent plane of chirality present in the starting carbohydrate. The synthetic pathway is used for the preparation and biological evaluation of cyclophellitol analogues in both enantiomeric series.

Other natural products currently under investigation in our group include anticancer agents pancratistatin, podophyllotoxin and camptothecin.

2. Development of Synthetic Methodology

In this area our interests encompass:

(a) Development of stereoselective methods and predictive stereochemistry models. For example, the stereochemical course of the conjugate addition reactions of organocuprates to gamma-alkoxy-alpha, beta-enoates has been studied in detail and the “Reductive Elimination” stereochemistry model has been put forward for use by the synthetic chemistry community.

(b) Discovery and investigation of multicomponent reactions (MCRs). Methods have been developed to synthesize diversely substituted pyridines, dihydropyridines or pyranopyridines.

Another MCR leads to the synthesis of various indenoheterocycles.

3. Rational Drug Design

A number of projects are underway involving synthesis and biological evaluation of libraries of compounds based on “privileged medicinal scaffolds.” A notable example is the discovery of a library of dihydropyridopyrazoles based on the pharmacophore derived from the potent anticancer agent podophyllotoxin. The library of analogues is accessible by a one-step multicomponent synthesis and the selected library members rival the natural product in cytotoxic potency and magnitudes of apoptosis induction in human cancer cells.

4. Biological Activity – Guided Natural Product Isolation

In collaboration with Professors Antonio Evidente (University of Naples, Italy) and Wim Steelant (New Mexico Tech) projects are underway to identify active constituents in medicinal plants of the Southwest, used by the Native Indians for a variety of maladies. Plant extracts have been obtained which possess potent antiproliferative, antiinvasive, antibacterial and antiviral activities. Identification of the small molecule constituents responsible for these activities is followed by the NMR structure elucidation and their independent synthesis.