Development of tetrahydroisoquinoline-based hydroxamic acid derivatives: potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities.
Development of tetrahydroisoquinoline-based hydroxamic acid derivatives: potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities.
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DOI：
10.1021/jm101605z
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发表时间：
2011-04
影响因子：
7.3
通讯作者：
Yingjie Zhang;Jinhong Feng;Yuping Jia;Xuejian Wang;Lei Zhang;Chunxi Liu;H. Fang;Wenfang Xu
中科院分区：
文献类型：
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作者：
Yingjie Zhang;Jinhong Feng;Yuping Jia;Xuejian Wang;Lei Zhang;Chunxi Liu;H. Fang;Wenfang Xu
组蛋白脱乙酰酶 (HDAC) 的抑制会导致几乎所有肿瘤细胞系的生长停滞、分化和凋亡，从而促进 HDAC 作为抗肿瘤治疗的有希望的靶标。在我们之前的研究中，我们开发了一系列新型1,2,3,4-四氢异喹啉-3-羧酸衍生物作为HDAC抑制剂（HDACi），其中化合物7d表现出良好的HDAC8抑制和抗增殖活性。在此，我们报告了一种新型四氢异喹啉异羟肟酸类似物作为潜在 HDACi 和抗癌药物的设计和开发。这些化合物的体外生物学评估显示出改善的 HDAC8 抑制（化合物 31a 和 31b 对 HDAC8 表现出中等 nMIC（50）值）和对多种肿瘤细胞系的有效生长抑制。最重要的是，与辛二酰苯胺异羟肟酸（SAHA）（一种已批准的 HDACi）相比，化合物 25e、34a 和 34b 在人乳腺癌（MDA-MB-231）异种移植模型中表现出优异的体内抗癌活性。总的来说，我们的结果表明带有异羟肟酸的四氢异喹啉是开发新型 HDACi 作为潜在抗癌剂的绝佳模板。
Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibitors (HDACi), among which compound 7d exhibited promising HDAC8 inhibitory and antiproliferative activities. Herein, we report the design and development of a new class of tetrahydroisoquinoline-bearing hydroxamic acid analogues as potential HDACi and anticancer agents. In vitro biological evaluation of these compounds showed improved HDAC8 inhibition (compounds 31a and 31b exhibited mid-nM IC(50) values against HDAC8) and potent growth inhibition in multiple tumor cell lines. Most importantly, compounds 25e, 34a, and 34b exhibited excellent in vivo anticancer activities in a human breast carcinoma (MDA-MB-231) xenograft model compared with suberoylanilide hydroxamic acid (SAHA), an approved HDACi. Collectively, our results indicate that tetrahydroisoquinoline bearing a hydroxamic acid is an excellent template to develop novel HDACi as potential anticancer agents.