Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, AffiliatedMinistry of Education, Yanbian University College of Pharmacy, Yanji 133002, Jilin Province, China.
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
Molecules. 2019 Mar 2;24(5):884. doi: 10.3390/molecules24050884.
Emodin is a cell arrest and apoptosis-inducing compound that is widely distributed in different plants (rhubarb, aloe), lichens and terrestrial fungi, and also isolated from marine-derived fungi and marine sponge-associated fungi. In this study, we designed and synthesized a novel series of emodin derivatives by binding emodin to an amino acid using linkers of varying lengths and composition, and evaluated their anti-proliferative activities using HepG2 cells (human hepatic carcinoma), MCF-7 cells (human breast cancer) and human normal liver L02 cells. Most of these derivatives showed moderate to potent anti-proliferative activities. Notably, compound exhibited potent anti-proliferative activity against HepG2 cells with the half maximal inhibitory concentration (IC) value of 4.95 µM, which was enhanced 8.8-fold compared to the parent compound emodin (IC = 43.87 µM), and it also exhibited better selective anti-proliferative activity and specificity than emodin. Moreover, further experiments demonstrated that compound displayed a significant efficacy of inducing apoptosis through mitochondrial pathway via release of cytochrome c from mitochondria and subsequent activation of caspase-9 and caspase-3, inducing cell arrest at G0/G1 phase, as well as suppression of cell migration of tumor cells. The preliminary results suggested that compound could be a promising lead compound for the discovery of novel anti-tumor drugs and has the potential for further investigations as an anti-cancer drug.
大黄素是一种细胞停滞和凋亡诱导化合物，广泛分布于不同的植物（大黄、芦荟）、地衣和陆生真菌中，也从海洋来源的真菌和海洋海绵相关真菌中分离得到。在这项研究中，我们设计并合成了一系列新型大黄素衍生物，通过将大黄素与氨基酸结合，使用不同长度和组成的连接子，并用 HepG2 细胞（人肝癌）、MCF-7 细胞（人乳腺癌）和人正常肝 L02 细胞评估它们的抗增殖活性。这些衍生物大多数表现出中度至强的抗增殖活性。值得注意的是，化合物 对 HepG2 细胞表现出很强的抗增殖活性，其半数最大抑制浓度（IC）值为 4.95 µM，与母体化合物大黄素（IC = 43.87 µM）相比增强了 8.8 倍，并且它也表现出比大黄素更好的选择性抗增殖活性和特异性。此外，进一步的实验表明，化合物 通过从线粒体释放细胞色素 c 并随后激活 caspase-9 和 caspase-3，通过线粒体途径诱导细胞凋亡，从而导致细胞停滞在 G0/G1 期，并抑制肿瘤细胞的迁移，显示出显著的疗效。初步结果表明，化合物 可能是一种有前途的新型抗肿瘤药物的先导化合物，并且具有作为抗癌药物进一步研究的潜力。
