Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group.
Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group.
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DOI：
10.1039/c4md00401a
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Woster PM
中科院分区：
文献类型：
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作者：
Li Y;Woster PM
具有异羟肟酸或苯甲酰胺锌结合基团（ZBG）的小分子是研究最彻底的组蛋白脱乙酰酶（HDAC）抑制剂。然而，对异羟肟酸部分的药代动力学责任和苯甲酰胺HDAC抑制剂的苯胺部分的潜在代谢毒性的担忧刺激了旨在发现替代ZBG的研究努力。在这里，我们报告的2-（恶唑-2-基）苯酚部分作为一种新的ZBG，可用于生产化合物，是有效的HDAC抑制剂。已经合成了一系列具有这种新型ZBG的类似物，并且这些类似物对HDAC 1以及IIb类HDAC（HDAC 6和HDAC 10）表现出选择性抑制。化合物10在MV-4-11白血病细胞系中具有7.5 μM的IC 50值，并诱导与0.5 μM SAHA相当量的乙酰化组蛋白3赖氨酸9（H3 K9）和p21 Waf 1/CIP 1。化合物10在HDAC 2的活性位点中的建模表明，2-（恶唑-2-基）苯酚部分具有与苯甲酰胺HDAC抑制剂类似的锌结合模式。
Small molecules featuring a hydroxamic acid or a benzamide zinc binding group (ZBG) are the most thoroughly studied histone deacetylase (HDAC) inhibitors. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety and potential metabolic toxicity of the aniline portion of benzamide HDAC inhibitors have stimulated research efforts aimed at discovering alternative ZBGs. Here we report the 2-(oxazol-2-yl)phenol moiety as a novel ZBG that can be used to produce compounds that are potent HDAC inhibitors. A series of analogues with this novel ZBG have been synthesized, and these analogues exhibit selective inhibition against HDAC1 as well as the class IIb HDACs (HDAC6 and HDAC10). Compound 10 possesses an IC50 value of 7.5 μM in the MV-4-11 leukemia cell line, and induces a comparable amount of acetylated histone 3 lysine 9 (H3K9) and p21Waf1/CIP1 as 0.5 μM of SAHA. Modeling of compound 10 in the active site of HDAC2 demonstrates that the 2-(oxazol-2-yl)phenol moiety has a zinc-binding pattern similar to benzamide HDAC inhibitors.