抗癌天然产物土槿乙酸的对映选择性全合成研究

Pseudolaric acids are novel deterpenoids isolated from Cortex pseudolaricis by Chinese scientists in 1980's. Pseudolaric acid B (PLB) exhibited significant cytotoxic activities against numerous tumor cell lines and strong antifungal activity. Recent studies have also shown that pseudolaric acid B displays antiangiogenic properties in a variety of cancer cell lines including gastric carcinoma, liver, breast, colon, cervical, protate cancer and melanoma cells. To establish a comprehensive structure-activity relationship (SAR) and to obtain a large quantity of compounds for further biological platform testings, enantioselective synthetic study of pseudolaric acid B is to be conducted. In the process of study, Sharpless epoxidation and intramolecular [5 + 2] cycloaddition reaction will be used as the key transformations to enantioselectively construct the polycyclic skeleton of pseudolaric acid B. The proposal intends to solve the problem in the synthesis of pseudolaric acid B on a relatively large scale. It will facilitate more comprehensive SAR studies and promote discovering more active and safer pseudolaric acid analogues that might hopefully become an anticancer drug in the future.

土槿乙酸（Pseudolaric Acid B）是我国科学家在上世纪80年代从松科植物金钱松根皮中分离的一种新型二萜酸化合物，具有抗真菌、抗生育、抗血管生成的作用。近年来研究证实，土槿乙酸还具有抑制肝癌、乳腺癌、宫颈癌、前列腺癌等多种肿瘤细胞的增殖并诱导癌细胞凋亡的作用。为了研究这类化合物的构效关系并为相应的生物学研究提供足够的样品支持，本课题将开展对这类分子的对映性选择性全合成研究。我们研究的主要目标是该家族分子中活性最突出的土槿乙酸（Pseudolaric acid B），拟采用Sharpless环氧化、分子内[5+2]环加成反应等关键步骤来完成其多环体系的不对称构建，希望通过对该工作的开展来解决这类新型二萜酸化合物较大规模的不对称合成的难题，为深入研究其构效关系以及发现更加具有开发潜力的土槿乙酸结构类似物提供一种有效的途径。

土槿乙酸（Pseudolaric Acid B）是我国科学家在上世纪50年代从松科植物金钱松根皮中分离的一类新型二萜酸化合物，具有 抗真菌、抗生育、抗血管生成和抗肿瘤等作用。本课题展开了对这类分子的对映性全合成研究。我们采用Sharpless不对称环氧化反应；Ti(O-iPr)4催化下环氧的氰基开环反应；以及呋喃酮分子内[5+2]环化加成反应等完成了土槿皮乙酸多环体系骨架的不对称构建。这为这类化合物的不对称合成以及后续生物学研究打下了坚实的基础。