新墨西哥交酯型柠檬苦素类衍生物的发现与功能研究

Mixcanolides are a group of B-ring rearranged limonoids specifically found in the plants of Meliaceae family. Recently, our initially chemical study on the plants of Khaya senegalensis and Trichilia sinesnis (Meliaceae) have led to the isolation of number of mixcanolides. Biological tests on these mixcanolides revealed one of the compounds (1) showed very potent and selective inhibition on CB1 (cannabinoid receptor type 1) with the binding affinity of Ki = 200nM, while for CB2 (cannabinoid receptor type 2) its Ki is only 5uM. Several derivatives of compound 1 were thus prepared for the SAR study. CB1 is an important drug target for the treatment of obesity. Bioassay also showed that two compounds (7 and 9) significantly increased estrogen level by activating aromatase (CYP19), which is a key regulator for the estrogen synthesis. Estrogen deficiency is implicated in the ailments, such as menopause syndrome, osteoporosis and Alzheimer's disease. Based on our preliminary research, the current project will cover the chemical studies on the four plant sepecies of Khaya senegalensis, K. ivorensis and Trichilia sinesnis, and T. connarroides aiming to isolate a number of novel mexicanolide-type limonoids, elucidate the structures of these limonoids, and test their biological activities for inhibiting CB1 and activating aromatase. Modification and SAR study on biological active compounds are also scheduled. Our final target is identification of drug leads.

墨西哥交酯型柠檬苦素是指一大类B环重排的柠檬苦素类衍生物。近期，我们对非洲楝和茸果鹧鸪花进行了初步的化学研究，获得了一系列新墨西哥交酯型柠檬苦素类衍生物。生物活性筛选显示一个化合物具有极强的大麻受体CB1的抑制活性（Ki值为200 nM），且有良好的选择性（CB2的Ki值为5 uM），并对其进行了初步的结构优化和构效关系研究。CB1受体是减肥/抗代谢性疾病药物的重要靶标，其拮抗剂是目前国际上研究的热点。同时还发现两个化合物能显著增加芳香化酶活性，促进雌二醇生成。芳香化酶是雌激素合成过程中的限速酶，是治疗雌激素失调的重要药物靶标。在此基础上，本项目将对非洲楝和其亲缘植物西非桃花心木，以及茸果鹧鸪花和其同属植物鹧鸪花等4种植物中的墨西哥交酯型柠檬苦素类衍生物进行深入的化学和相关生物活性的研究，以发现结构新颖的活性物质，并对所获得的活性化合物进行结构优化和构效关系研究，以期发现药物先导结构。

本项目完成了9种药用植物化学成分的研究和生物活性测试，包括：茸果鹧鸪花 （Trichilia sinensis）、鹧鸪花（Trichilia connaroides）、西非桃花心木（Khaya ivorensis）、长序虎皮楠 (Daphniphyllum longeracemosum)、金刚纂（Euphorbia neriifolia L.）、海南叶下珠（Phyllanthus hainanensis Merr.）、灰毛浆果楝（Cipadessa cinerascens）、海南樫木（Dysoxylum mollissimum）和割舌树 (Walsura robusta)，共获得化合物180多个，其中新化合物近100个，新骨架化合物14个。所获得的化合物主要为萜类，其中大部分为新墨西哥交酯型柠檬苦素。经过生物活性筛选，发现各类活性化合物21个，包括抗HIV活性、抗炎、降脂、免疫抑制和抗肿瘤等。部分研究结果已发表学术论文10篇，申请专利1项。