The equilibrium between histone acetylation and deacetylation plays an important role in cancer initiation and progression. The histone deacetylases (HDACs) are a class of key regulators of gene expression that enzymatically remove an acetyl moiety from acetylated lysine ε-amino groups on histone tails. Therefore, HDAC inhibitors have recently emerged as a promising strategy for cancer therapy and several pan-HDAC inhibitors have globally been approved for clinical use. In the present study, we designed and synthesized a series of substituted indole-based hydroxamic acid derivatives that exhibited potent anti-proliferative activities in various tumor cell lines. Among the compounds tested, compound 4o, was found to be among the most potent in the inhibition of HDAC1 (half maximal inhibitory concentration, IC₅₀ = 1.16 nM) and HDAC6 (IC₅₀ = 2.30 nM). It also exhibited excellent in vitro anti-tumor proliferation activity. Additionally, compound 4o effectively increased the acetylation of histone H3 in a dose-dependent manner and inhibited cell proliferation by inducing cell cycle arrest and apoptosis. Moreover, compound 4o remarkably blocked colony formation in HCT116 cancer cells. Based on its favorable in vitro profile, compound 4o was further evaluated in an HCT116 xenograft mouse model, in which it demonstrated better in vivo efficacy than the clinically used HDAC inhibitor, suberanilohydroxamic acid. Interestingly, compound 4k was found to have a preference for the inhibition of HDAC6, with IC₅₀ values of 115.20 and 5.29 nM against HDAC1 and HDAC6, respectively.

组蛋白乙酰化和去乙酰化之间的平衡在癌症的发生和发展中起重要作用。组蛋白去乙酰化酶 (HDAC) 是一类基因表达的关键调节剂，可从组蛋白尾部的乙酰化赖氨酸ε -氨基中酶促去除乙酰基。因此，HDAC 抑制剂最近已成为一种有前途的癌症治疗策略，并且几种泛 HDAC 抑制剂已在全球范围内被批准用于临床。在本研究中，我们设计并合成了一系列取代的吲哚基异羟肟酸衍生物，这些衍生物在各种肿瘤细胞系中表现出有效的抗增殖活性。在测试的化合物中，化合物4o, 被发现是抑制 HDAC1 (半最大抑制浓度, IC ₅₀  = 1.16 nM) 和 HDAC6 (IC ₅₀  = 2.30 nM) 最有效的化合物之一。它还表现出优异的体外抗肿瘤增殖活性。此外，化合物4o以剂量依赖性方式有效增加组蛋白 H3 的乙酰化，并通过诱导细胞周期停滞和细胞凋亡来抑制细胞增殖。此外，化合物4o显着阻断了 HCT116 癌细胞的集落形成。基于其良好的体外特征，化合物4o在 HCT116 异种移植小鼠模型中进行了进一步评估，其中它在体内表现得更好疗效优于临床上使用的HDAC抑制剂次氨基羟肟酸。有趣的是，发现化合物4k具有抑制 HDAC6 的偏好，对 HDAC1 和 HDAC6 的 IC ₅₀值分别为 115.20 和 5.29 nM。