Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compound 11a exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using 11a as a lead. Representative compound 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compound 13e exhibited low nanomolar IC₅₀s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC₅₀ of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compound 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.

中文翻译：

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I类HDAC抑制剂根据其p53状态在白血病和前列腺癌细胞中显示出不同的抗肿瘤机制

以前，我们设计并合成了一系列基于邻氨基苯甲酰胺的组蛋白脱乙酰基酶（HDAC）抑制剂，其中代表性的化合物11a对I类HDAC表现出有效的抑制活性。在这项研究中，我们报告了使用11a作为先导，开发了更有效的基于酰肼的I类选择性HDAC抑制剂。代表性化合物13b对HDAC1、2和3表现出混合，缓慢和紧密的结合抑制机制。最有效的化合物13e对HDAC1、2和3表现出低的纳摩尔IC ₅₀ s，并且可以下调急性髓细胞白血病中的HDAC6。 MV4-11细胞。欧盟委员会₅₀的13EMV4-11细胞的抗性为34.7 nM，比其母体化合物11a低26倍。体外对13e的反应根据细胞类型而显着变化，并且有趣的是：在p53野生型MV4-11细胞中，13e通过凋亡和G1 / S细胞周期停滞诱导了细胞死亡，这很可能是由p53依赖性途径介导的，而在没有p53的PC-3细胞中，13e导致G2 / M停滞并抑制细胞增殖，而不诱导caspase-3依赖性细胞凋亡。