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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors
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Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors

机译：基于嘌呤/嘌呤肌肉疗效的支架作为HDAC抑制剂的苯甲酰胺类的新衍生物

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摘要

This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 mu M), MDA-MB-468 (IC50 = 0.65 mu M), and liver cancer cells HepG2 (IC50 = 2.44 mu M), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 mu M) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 mu M respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents. (C) 2020 Published by Elsevier Masson SAS.
机译：本研究报告了含有嘌呤/嘌呤肌腱的一系列组蛋白脱乙酰化酶（HDAC）抑制剂的设计，合成和评价，作为封端基团和N-（2-氨基苯基） - 苯甲酰甲酰胺单元。体外细胞毒性研究表明，苯甲酰胺14抑制了三阴性乳腺癌细胞MDA-MB-231（IC50 =1.48μm）的生长，MDA-MB-468（IC50 =0.65μm）和肝癌细胞Hepg2（ IC50 = 2.44 mu m），优于MS-275（5）和赤酰胺（6）。与众所周知的HDAC抑制剂SAHA相比，14在三种白血病细胞系，K-562，KG-1和THP-1中显示出更高的毒性（IC50 =0.33μm）。此外，在HDAC敏感性和胃细胞系，YCC11和YCC3 / 7中，14的发现分别是致毒性，表示克服HDACI抗性的电位。此外，大致抑制作用比MS-275（5）和赤酰胺（6）更明显，14升至HDAC1,2和3同种型，分别为0.108,0.585和0.563μm的IC 50值。化合物14还表现出人MDA-MB-231乳腺癌异种移植小鼠模型中有效的抗肿瘤功效，为抗癌剂的发育提供了潜在的潜在铅。 （c）2020由Elsevier Masson SA发表。

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