IIa 类组蛋白脱乙酰酶 (HDAC) 与多种癌症的肿瘤发生有关。此前，我们设计了苯基异羟肟酸 LH4f 作为一种有效的 IIa 类 HDAC 抑制剂。然而，它也无选择性地抑制 I 类和 IIb 类 HDAC。为了增强化合物对 IIa 类 HDAC 的选择性，将选择性 HDAC7 抑制剂 1 的邻苯基纳入 LH4f 中苯基异羟肟酸的邻位。与 LH4f 相比，大多数所得化合物对 IIa 类 HDAC 的选择性显着提高。值得注意的是，化合物 7g 表现出最强的 HDAC9 抑制作用，IC50 值为 40nM。分子模型进一步确定了化合物 7 g 与 HDAC9 结合的关键相互作用。化合物 7 g 显着抑制多种人类癌细胞，诱导细胞凋亡，调节 caspase 相关蛋白以及 p38，并引起 DNA 损伤。这些发现表明 IIa 类 HDAC 抑制剂作为开发癌症治疗药物的先导化合物的潜力。

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.