抗疟疾乌药烷二聚倍半萜的发现与研究

Malaria is a global parasitic infectious disease caused by Plasmodium parasites, which are transmitted by the bite of female Anopheles mosquitoes. An estimated 212 million malaria cases and 429, 000 deaths were reported in 2015 alone, indicating malarial is still a serious public health problem that needs the discovery of new anti-malarial drugs. Lindenane disesquiterpenoids are a group of dimers from two molecular lindenane sesquiterpenoids by the endo-Diels-Alder cycloaddition reaction, specially found in the plants of Meliaceae family. Recently, our study on the anti-malarial plant chloranthus fortunei have led to the isolation of number lindenane disesquiterpenoids, three of which are with new carbon skeletons. Those disesquiterpenoids showed obvious anti-malarial activities, and preliminary structure-activity relationship study were taken. For the inspiring pioneer studies, the chemical and biological investigations on the three plant species of Chloranthus fortunei, Chloranthus holostegius, and Sarcandra glabra, were proposed by the project in order to discover the new natural compounds with significant bioactivities, especially the anti-malarial disesquiterpenoids. Thorough structure-activity relationship and anti-malarial mechanism of those disesquiterpenoids were explored to find the optimal compounds, which may be developed as new anti-malarial medicine leads or drug candidates as our terminal target.

疟疾是一种由疟原虫造成的，以按蚊为主要媒介传播的全球性急性寄生虫传染病。2015年全球共有2.12亿疟疾新病例，死亡人数约为42.9万人，可见疟疾仍然是一个严重的公共卫生问题，抗疟药物的研发非常重要。乌药烷型二聚倍半萜是两分子乌药烷型倍半萜通过endo-Diels-Alder环加成反应形成的一类化合物，多分布于金粟兰科植物。近期，我们对民间抗疟疾的丝穗金粟兰进行了研究，发现了系列具有极强抗疟作用的乌药烷型二聚倍半萜，包括3个骨架新颖化合物，并初步认识其抗疟疾的构效关系。在此基础上，本项目拟对丝穗金粟兰以及其亲缘植物全缘金粟兰和草珊瑚等植物进行系统的化学和抗疟疾活性研究，以期发现结构新颖、具有显著疟疾活性的二聚倍半萜类化合物，并对重要活性化合物进行结构优化和更深入的构效关系研究，以期发现药物先导或药物候选，并对其作用机制进行探讨。

疟疾是三大传染病之一，并且疟原虫对所有一线抗疟药物都产生了耐药性，急需研发新型抗疟疾药物。我们前期研究发现金粟兰科植物富含一类乌药烷型二聚倍半萜，具有显著的抗疟疾作用。在此基础上，本项目已经完成了4种金粟兰科植物（全缘金粟兰、海南草珊瑚、金粟兰和雪香兰）和2种相关药用植物（西印度醋栗和肉桂）的化学成分研究，分离鉴定各种类型的化合物250个，其中新化合物60个，新骨架化合物10个。发现各类活性化合物20个，包括抗疟疾、抗肿瘤、NF-kB抑制活性等。重点筛选了抗疟疾活性，获得了抗疟疾活性化合物12个，包括6个纳摩尔级抗疟疾化合物，其中一个分子的抗疟疾活性可达皮摩尔级，并且具有非常高的安全指数，被列入后续研究的候选分子。同时我们对抗疟疾先导分子进行了结构优化，获得了20个衍生物，并对其构效关系进行了总结。目前，重要活性化合物仍在进行生物作用机制、结构优化、仿生合成和构效关系研究。通过本项目研究，扩大了抗疟疾乌药烷型二聚倍半萜库，加深了对该类结构的构效关系以及抗疟疾作用机制认识，为后续结构改造和药物研发提供了依据和启示。系列研究结果已在Sci. China: Chem.、Org. Chem. Front.、Org. Lett.、ACS Infect. Dis.、Tetrahedron和Tetrahedron Lett.上发表高质量研究论文6篇；授权专利3件。