Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment
Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment
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反苯环丙明衍生物的设计和合成作为新型LSD1/HDACs双重抑制剂用于癌症治疗
DOI：
10.1016/j.ejmech.2017.09.038
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发表时间：
2017-11-10
影响因子：
6.7
通讯作者：
Guan, Yuan-Yuan
中科院分区：
文献类型：
--
作者：
Duan, Ying-Chao;Ma, Yong-Cheng;Guan, Yuan-Yuan
赖氨酸特异性脱甲基酶1(LSD1)和组蛋白脱乙酰基酶(HDAC)是治疗癌症的有效药物靶点。最近的研究揭示了LSD1和HDAC之间的重要功能相互作用，并且有证据表明LSD1和HDAC联合抑制剂对癌症具有协同作用。因此，开发针对LSD1和HDACs的抑制剂可能是癌症表观遗传治疗的一种有前途的策略。本文报道了一系列三羟甲基环丙胺类化合物作为LSD1/HDACs双重抑制剂的合成。大部分化合物显示出较强的LSD1和HDACs抑制活性，特别是化合物7对HDAC1和HDAC2的抑制活性最强，IC50分别为15 nM和23 nM，对LSD1的抑制作用最强，IC50为1.20 mU M。化合物7对MGC-803、MCF-7、SW-620和A-549人癌细胞的IC50为0.81~4.28 mU M，对MGC-803、MCF-7、SW-620和A-549人癌细胞具有较强的抑制作用。进一步的机制研究表明，化合物7对MGC-803细胞的作用呈剂量依赖性地增加细胞H3K4和H3K9的甲基化，以及H3的乙酰化，降低线粒体膜电位并诱导显著的细胞凋亡。对接研究表明，化合物7可以很好地对接到LSD1和HDAC2的活性结合部位。这一发现突出了LSD1/HDACs双重抑制剂作为新型抗癌药物的开发潜力。(C)2017年爱思唯尔·马森公司。版权所有。
Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors. Most compounds showed potent LSD1 and HDACs inhibitory activity, especially compound 7 displayed the most potent inhibitory activity against HDAC1 and HDAC2 with IC50 of 15 nM and 23 nM, as well as potent inhibition against LSD1 with IC50 of 1.20 mu M. Compound 7 demonstrated stronger anti-proliferative activities than SAHA with IC50 values ranging from 0.81 to 4.28 mu M against MGC-803, MCF-7, SW-620 and A-549 human cancer cell lines. Further mechanistic studies showed that compound 7 treatment in MGC-803 cells dose-dependently increased cellular H3K4 and H3K9 methylation, as well as H3 acetylation, decreased the mitochondrial membrane potential and induced remarkable apoptosis. Docking studies showed that compound 7 can be well docked into the active binding sites of LSD1 and HDAC2. This finding highlights the potential for the development of LSD1/HDACs dual inhibitors as novel anticancer drugs. (C) 2017 Elsevier Masson SAS. All rights reserved.