Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity.
Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity.
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DOI：
10.3390/ijms23010369
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发表时间：
2021-12-29
影响因子：
5.6
通讯作者：
Sippl W
中科院分区：
文献类型：
--
作者：
Ibrahim HS;Abdelsalam M;Zeyn Y;Zessin M;Mustafa AM;Fischer MA;Zeyen P;Sun P;Bülbül EF;Vecchio A;Erdmann F;Schmidt M;Robaa D;Barinka C;Romier C;Schutkowski M;Krämer OH;Sippl W
I类组蛋白脱乙酰酶（HDAC）是细胞增殖的关键调节剂，并且它们在癌细胞中经常失调。我们在这里报告了一系列新的I类选择性HDAC抑制剂（HDACi）的合成含有2-氨基苯甲酰胺部分作为锌结合基团与中央（哌嗪-1-基）吡嗪或（哌嗪-1-基）嘧啶部分连接。一些化合物另外被芳族封端基团取代。在体外针对人HDAC 1、2、3和8酶测试了化合物，并与参考I类HDACi（恩蒂诺他（MS-275）、莫西蒂诺他、CI 994和RGFP-966）进行了比较。发现最有前途的化合物对HDAC 1、2和3的选择性高于来自其他类别的剩余HDAC亚型。分子对接研究和MD模拟进行合理化的体外数据，并推导出一个完整的构效关系（SAR）分析，这一新的系列I类HDACi。选择最有效的化合物，包括阻断HDAC 1、HDAC 2和HDAC 3的19 f，以及选择性HDAC 1/HDAC 2抑制剂21 a和29 b，用于针对人急性髓性白血病（AML）和红白血病癌（HEL）细胞的进一步细胞测试，考虑到它们对人胚胎HEK 293细胞的低毒性。我们发现19 f上级临床测试的I类HDACi Entinostat（MS-275）。因此，19 f是一种新的特异性HDACi，具有消除各种来源的血液癌细胞的潜力。
Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
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对复发或难治性淋巴瘤中的组蛋白脱乙酰基酶抑制剂的2阶段研究。
影响因子：
6.5
作者：
Batlevi CL;Crump M;Andreadis C;Rizzieri D;Assouline SE;Fox S;van der Jagt RHC;Copeland A;Potvin D;Chao R;Younes A
通讯作者：
Younes A
影响因子：
6.1
作者：
Padrnos L;Mesa R
通讯作者：
Mesa R
影响因子：
11.5
作者：
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通讯作者：
Angibaud, Patrick
影响因子：
4
作者：
Fan, Jing;Krautkramer, Kimberly A.;Feldman, Jessica L.;Denu, John M.
通讯作者：
Denu, John M.
影响因子：
4.2
作者：
Gryder BE;Sodji QH;Oyelere AK
通讯作者：
Oyelere AK