CHEMISTRY OF NATURAL PRODUCTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。研究兴趣涉及天然产物化学的方方面面，包括它们的分离、结构确定、合成和生物活性。他的团队与人类学家、植物学家、药理学家和微生物学家合作，研究了来自巴基斯坦、玻利维亚和中国的特有药用植物，作为药物开发的先导化合物来源。这些活性化合物的分离包括制备和分析层析，并通过抗癌、抗HIV、抗细菌、抗真菌、抗锥虫、杀虫和中枢神经系统活性的生物测试进行指导。结构的确定在很大程度上依赖于核磁共振、质谱学、紫外光谱和红外光谱等方法。合成是为了提供更多的活性化合物用于生物评价，确定结构-活性相关性，并通过适当的同位素标记，研究生化作用机制。最近发现和研究了几种具有抗癌、抗结核病、特别是抗艾滋病毒活性的先导化合物。最近的努力集中在研究最初在玻利维亚卡拉瓦亚印第安人使用的几种药用植物中发现的具有抗艾滋病毒活性的化合物。从四种不同植物中分离得到的四种不同活性化合物都是奎尼酸的二咖啡酰衍生物[DCQA]。值得注意的是，它们的抗HIV活性被证明是由于对整合酶的抑制，整合酶是已知的三种病毒酶中唯一一种[其他是逆转录酶和蛋白酶]，而药物尚不清楚。合成了一种简单的DCQA类似物--二咖啡酰酒石酸，它也被证明是HIV-1整合酶的选择性抑制剂，因此被选为正在进行的通过抑制HIV整合酶而抗HIV活性的构效关系的合成研究的先导化合物。

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.