Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides
Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides
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DOI：
10.1021/jm049002a
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发表时间：
2005-05-05
影响因子：
7.3
通讯作者：
Brosch, G
中科院分区：
文献类型：
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作者：
Mai, A;Massa, S;Brosch, G
对芳酰基-吡咯基-羟基酰胺 (APHA) 进行化学操作，得到(芳基氧代丙烯基)吡咯基异羟肟酸酯 2a-w，并测定了它们对玉米 HDAC 的抑制作用及其 I 类或 II 类 HDAC 选择性。特别是，从这些研究中，一些苯间位取代的化合物成为高度 II 类 (IIa) 选择性 HDAC 抑制剂，其中选择性最高的是 3-氯和 3-氟取代的化合物 2c (SI = 71.4) 和 2f (SI = 176.4)。用 1-萘环取代苯得到 2s，对 II 类同源物 HD1-A 具有高度活性 (IC50 = 10 nM)，但 II 类选择性低于 2c,f 当针对人 HDAC1 和 HDAC4 进行测试时，2f 对 HDAC1 没有抑制活性，但能够抑制 HDAC4。此外，在人类 U937 急性髓性白血病细胞中，2f 对细胞凋亡、粒细胞分化和细胞周期没有产生任何影响，而 2s（保留 I 类 HDAC 抑制活性）的效力比用作参考的 SAHA 低 2 倍。
Chemical manipulations performed on aroyl-pyrrolyl-hydroxyamides (APHAs) led to (aryloxopropenyl)pyrrolyl hydroxamates 2a-w, and their inhibition against maize HDACs and their class I or class II HDAC selectivity were determined. In particular, from these studies some benzene meta-substituted compounds emerged as highly class II (IIa)-selective HDAC inhibitors, the most selective being the 3-chloro- and 3-fluoro-substituted compounds 2c (SI = 71.4) and 2f (SI = 176.4). The replacement of benzene with a 1-naphthyl ring afforded 2s, highly active against the class II homologue HD1-A (IC50 = 10 nM) but less class II-selective than 2c,f When tested against human HDAC1 and HDAC4, 2f showed no inhibitory activity against HDAC1 but was able to inhibit HDAC4. Moreover, in human U937 acute myeloid leukaemia cells 2f did not produce any effect on apoptosis, granulocytic differentiation, and the cell cycle, whereas 2s (that retain class I HDAC inhibitory activity) was 2-fold less potent than SAHA used as reference.