This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Research interests involve all aspects of the chemistry of natural products including their isolation, structure determination, synthesis and biological activity. Working in collaboration with anthropologists, botanists, pharmacologists, and microbiologists his group examines characterized medicinal plants from Pakistan, Bolivia and China as sources of lead compounds for drug development. Isolation of these active compounds involves preparative and analytical chromatography and is directed by bioassays for anti-cancer, anti-HIV, anti-bacterial, anti-fungal, anti-trypanosomal, insecticidal and CNS activity. Structure determination relies heavily on NMR, mass spectral, UV and IR methods. Syntheses are undertaken to supply additional active compounds for biological evaluation, to determine structure-activity correlations and, with appropriate isotopic labeling, to study biochemical mechanisms of action. Several lead compounds with anti-cancer, anti-TB and, especially, anti-HIV activity have recently been found and studied. Recent efforts have centered on studies of compounds with anti-HIV activity originally detected in several medicinal plants used by the Kallawaya Indians of Bolivia. Four different active compounds isolated from four different plants all turned out to be dicaffeoyl derivatives of quinic acid [DCQA's]. Significantly their anti-HIV activity was shown to be due to the inhibition of integrase, the only one of three known viral enzymes [the others being reverse transcriptase and protease] for which no drugs were known. Chicoric acid [dicaffeoyltartaric acid], a simple analogue of DCQA, was synthesized, also shown to be a selective inhibitor of HIV-1 Integrase and therefore was chosen as the lead compound for an on-going synthetic study of the structure-activity relationships responsible for anti-HIV activity by inhibition of HIV-integrase.
Showing the most recent 10 out of 696 publications
