瑞香狼毒植物中C-3/C-3”联结双二氢黄酮衍生物的设计合成及其抗肿瘤构效关系研究

Stellera chamaejasme L., member of Thymelaeaceae, is a well-known traditional Chinese herbal medicine. Our previous study revealed that C-3/C-3"-biflavanones of this plant showed obvious anti-tumor activity as well as high security. Further biological evaluation exhitited that some derivatives were able to induce apoptosis of nonsmall cell lung cancer cell line A549 and arrest the cell cycle in G0-G1 phase. Therefore, it is of great importance to do more in-depth research of C-3/C-3"-biflavanones. On the basis of our previous study, this project will design a series of analogues based on the lead compound chamaejasmenin B (2) with the adoption of preliminary structure-activity relationship study and classic drug design theory. The chemical modification will mainly focus on the positions 7, 7", 8, 8" with the expectation of enhancing their anti-tumor efficacy. Then with the help of the evaluation of the in vitro and in vivo anti-tumor activity of these derivatives, the more detailed structure-activity relationships of these compounds may be obtained. Besides, further study focused on the anti-tumor mechanism of C-3/C-3"-biflavanone derivatives may bring about high opportunity of finding several excellent lead compounds with high efficacy and low toxicity. And eventually, novel anticancer drug candidates with independent intellectual property rights will be obtained. The anti-tumor activity of Stellera chamaejasme L. has been proved by widely use as folk medicine. Through the studies of this Project, the exactly ingredients of this plant which shows anti-tumor activity will be clearly defined.

瑞香狼毒隶属于瑞香科植物，为我国有名的传统中药。在前期工作中本课题组发现该植物中C-3/C-3"双二氢黄酮具有显著的抗肿瘤活性，兼具较高的安全性。同时我们还发现该类成分能够显著诱导人非小细胞肺癌 A549 细胞凋亡和阻滞A549 细胞周期于G1/G0期。因此对该类成分的深入研究具有重要意义。本项目在前期工作的基础上，参考初步构效关系和经典药物设计理论，拟对活性先导物狼毒宁B(2)进行系列衍生化设计，主要对结构中的7、7"、8、8"位进行结构优化，期望增加其抗肿瘤活性，并结合体内外抗肿瘤活性试验，得出此类成分的抗肿瘤构效关系。此外，我们将进一步研究该类双二氢黄酮抗肿瘤分子作用机制，以期发现一些高效低毒抗肿瘤活性的先导物，并期望最终能得到具有自主知识产权的新型抗癌活性候选药物。 瑞香狼毒的抗癌活性已被广泛的民间用药所证明，通过本项目的研究，可以阐明该植物中具有抗肿瘤活性的确切成分。

瑞香狼毒为我国著名传统中药，具有较大毒性。本项目在对该植物的乙酸乙酯提取物和正丁醇提取物进行植化分离，得到18个天然产物，其中三个为新化合物，并首次确定了三种C-3/-3"双二氢黄酮类化合物骨架的绝对构型。通过对化合物chamaejasmenin B和狼毒色原酮进行结构修饰，共获得40余个黄酮类衍生化，结合体外抗肿瘤活性筛选，其中具有C-3/C-3"联结双二氢黄酮骨架的天然产物及其衍生物具有较显著的抗肿瘤活性，总结得出构效关系。进一步对抗肿瘤活性明显的双二氢黄酮成分chamaejasmenin B和neochamaejasmin C进行较系统的抗肿瘤作用机制的研究，研究结果表明此类天然产物具有诱导DNA损伤的作用，并且在较高浓度能诱导人非小细胞肺癌A549细胞和骨肉瘤KHOS细胞发生凋亡，进一步的作用机制研究表明该类成分能阻滞A549细胞于G1/G0期。. 本项目的研究阐明了瑞香狼毒植物的抗肿瘤活性成分，得到数个具有重要价值的抗肿瘤活性双黄酮成分，可变废为宝的利用该植物，这对我国中药现代化也具有一定的现实意义。