Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
Bioorg Med Chem. 2019 Jan 15;27(2):370-374. doi: 10.1016/j.bmc.2018.12.013. Epub 2018 Dec 7.
Lysine-specific demethylase 1 (LSD1) has recently emerged as a therapeutic target for cancer. However, almost all LSD1 inhibitors developed to date are chemo-synthesised molecules. In this study, the LSD1 inhibitory activity of 12 natural flavones, including four aglycones and their corresponding monoglycosides and diglucosides, was evaluated. Based on the structure-activity relationships, LSD1 inhibition activity was greater for flavonoid monoglycosides than their aglycones lacking the sugar moiety. The effects of isoquercitrin, which exhibited optimal LSD1 inhibitory activity, on cancer cell properties were evaluated. Isoquercitrin induced the expression of key proteins in the mitochondrial-mediated apoptosis pathway and caused apoptosis in LSD1-overexpressing MDA-MB-231 cells via the inhibition of LSD1. These findings suggest that natural LSD1 inhibitors, and particularly isoquercitrin, are promising for cancer treatment.
赖氨酸特异性去甲基化酶 1（LSD1）最近成为癌症治疗的一个靶点。然而，迄今为止开发的几乎所有 LSD1 抑制剂都是化学合成的分子。在这项研究中，评估了 12 种天然类黄酮（包括 4 种苷元和它们相应的单糖苷和双糖苷）对 LSD1 的抑制活性。基于构效关系，类黄酮单糖苷对 LSD1 的抑制活性大于缺乏糖部分的苷元。评估了具有最佳 LSD1 抑制活性的异槲皮苷对癌细胞特性的影响。异槲皮苷诱导线粒体介导的细胞凋亡途径中的关键蛋白的表达，并通过抑制 LSD1 导致 LSD1 过表达的 MDA-MB-231 细胞凋亡。这些发现表明，天然 LSD1 抑制剂，特别是异槲皮苷，有望用于癌症治疗。
