Anti-tumor effects and 3D-quantitative structure-activity relationship analysis of bufadienolides from toad venom
Anti-tumor effects and 3D-quantitative structure-activity relationship analysis of bufadienolides from toad venom
复制标题
蟾蜍毒二烯内酯的抗肿瘤作用及3D定量构效关系分析
DOI：
10.1016/j.fitote.2019.03.006
复制
发表时间：
2019-04-01
期刊：
影响因子：
3.4
通讯作者：
Yu, Zhi-Ling
中科院分区：
文献类型：
--
作者：
Liu, Jun-Shan;Deng, Li-Juan;Yu, Zhi-Ling
蟾蜍毒液（venenum bufonis，也叫蟾酥）在中国被广泛用于治疗各种疾病，特别是癌症。蟾蜍二烯内酯类化合物是蟾蜍毒抗肿瘤作用的主要成分。然而，这些蟾蜍毒素的化学组成、细胞毒性和关键药效团至今尚未明确。丰富对蟾蜍二烯内酯多样性的认识，从蟾酥中寻找活性更好的蟾蜍二烯内酯。本研究采用MTT法、流式细胞术和Western blotting等方法对中药复方中的化学成分进行了分离，研究了其抗肿瘤作用及其机制，并建立了CoMFA和CoMSIA定量构效关系（QSAR）模型，以阐明中药复方中化学结构与细胞毒性之间的重要关系。在47个天然蟾蜍二烯内酯类化合物中，大部分化合物（本研究分离的21个化合物和以前分离的26个化合物）对肿瘤细胞有明显的抑制作用，其中化合物1、8、12、18和19对4种肿瘤细胞的抑制活性最强。化合物18诱导G2/M期细胞周期阻滞和凋亡。此外，从CoMFA和CoMSIA生成的3D等高线图确定了几个负责抗肿瘤活性的蟾蜍二烯内酯的药效团。本研究为蟾蜍二烯内酯类化合物的结构修饰和合理药物设计提供了可靠的信息。
Toad venom (venenum bufonis, also called Chan'su) has been widely used for centuries in China to treat different diseases, especially for cancer. Bufadienolides are mainly responsible for the anti-cancer effects of toad venom. However, systematic chemical composition and cytotoxicity as well as key pharmacophores of these bufadie-nolides from toad venom have not yet been defined clearly. To enrich the understanding of the diversity of bufadienolides and to find bufadienolides with better activities from toad venom. This study was carried out to isolate chemical constituents, research their anti-tumor effects and mechanisms by MTT assay, flow cytometry and Western blotting, and develop a CoMFA and CoMSIA quantitative structure-activity relationship (QSAR) model for illustrating the vital relationship between the chemical structures and cytotoxicities. Among 47 natural bufadienolides, most of bufadienolides (21 compounds isolated in this study and 26 compounds isolated previously) could significantly inhibit the proliferation of cancer cells, and compounds 1, 8, 12, 18 and 19 showed the most potent inhibitory activity against four types of human tumor cells. Compound 18 induced G(2)/M cell cycle arrest and apoptosis. Moreover, 3D contour maps generated from CoMFA and CoMSIA identified several pharmacophores of bufadienolides responsible for the anti-tumor activities. Our study might provide reliable information for future structure modification and rational drug design of bufadienolides with anticancer activities in medical chemistry.