非核苷类HIV-1逆转录酶抑制剂Stachybotrin D，Stachybotrysin G及其类似物的全合成和构效关系研究

HIV virus is the genetic variation in human pathogens, pathogens, with a high reproduction, high mutation, high reorganization. NNRTIs are important components for highly active antiretroviral therapy (HAART). NNRTI-resistant mutations exist widely and spread in clinical settings over the past decade. Therefore, there remains a strong demand for the development of new NNRTIs that can effectively inhibit NNRTI-resistant viruses..This project focuses on the syntheses of Stachybotrin D，Stachybotrysin G and derivatives，which were isolated from bioactive secondary metabolites from sponge-associated microorganisms and have proven to have good biological activities. The anti-HIV activity of Stachybotrin D is 200-300 times than multi-resistant HIV combination of Nevirapine. These would need to develop a unified strategy that enables the divergent syntheses of sesquiterpenoid skeletons with high step-economy and overall efficiency. Furthermore, we will facilitate a relative large-scale synthesis which would bring enough materials for the further structure-activity relationship studies. In addition, we are going to prepare a library of natural or “non-natural natural products” for drug discovery studies via the function-oriented synthesis (FOS)。

HIV病毒是人类最大遗传变异的病原体，具有高复制性，高变异性，高重组性。非核苷类逆转录酶抑制剂是临床高效抗逆转录病毒疗法治疗艾滋病的重要途径。目前，NNRTI的耐药突变一直广泛存在于临床一线用药使用中。因此，急需开发新型NNRTIs来解决其耐药突变问题。.本项目中，我们以近期从海绵共附生真菌中分离得的，结构新颖的逆转录酶抑制剂Stachybotrin D与Stachybotrysin G等倍半萜类海洋天然产物作为研究对象，其中Stachybotrin D抗HIV活性是多药耐药艾滋病毒的联合用药奈韦拉平（NVP）活性的100-300倍，进而发展一种高效的发散合成策略进行全合成，解决天然产物的药源问题。此外，使用功能导向合成（FOS）策略，对天然产物进行结构改造，设计出更优良活性表现的“非天然的天然产物”用于进一步相关药学研究，以期研发出药效更佳更适于临床应用的新药。

倍半萜作为一类重要的活性先导化合物，用于开发具有自主知识产权的创新药物扮演着重要的角色。针对这类海洋天然产物获取困难，生物活性丰富等特点，我们设计了可以潜在放大的合成路线，解决其后续药学研究的药源问题。通过以廉价易得的天然产物齐墩果酸为原料，对含有这类骨架的天然产物(+)-Arisugacins F, G实现了简洁、高效的合成。此外，我们在研究十氢萘环和侧链两部分偶联方法的过程中，通过钯催化的stille偶联顺利完成了天然产物Isohericenone J及其类似物的首次全合成研究，上述工作为合成这类骨架天然产物提供了新的合成思路。在研究本项目既定研究计划的基础上，与本单位优势学科药物化物领域进行交叉合作研究，我们发展了一系列方法学高效建立了磺酰胺类小分子化合物库，为本课题组解决了抗病毒等相关药学研究提供了丰富的物质基础。