Inhibition of histone deacetylases (HDACs) has been extensively studied in the development of anticancer drugs. In the discovery of potent HDAC inhibitors with novel structures, the 2-substituted phenylquinoline-4-carboxylic acid group was introduced to the cap moiety of HDAC inhibitors. In total, 30 compounds were synthesized with hydroxamic acid or hydrazide zinc-binding groups. In the enzyme inhibitory test, active compound D28 and its analog D29 exhibited significant HDAC3 selectivity against HDAC1, 2, 3, and 6. However, compared with D28, the hydrazide-bearing compounds (D29 and D30) with remarkably improved enzyme inhibitory activities did not exhibit significant antiproliferative potency in the in vitro anticancer study. Further K562 cell-based mechanistic results revealed that induction of G2/M cell cycle arrest and promotion of apoptosis make important contributions to the anticancer effects of molecule D28. Collectively, an HDAC3 selective inhibitor (D28) with potent in vitro anticancer activity was developed as a lead compound for the treatment of cancer.

组蛋白脱乙酰酶 (HDAC) 的抑制作用已在抗癌药物的开发中得到广泛研究。在发现具有新结构的强效 HDAC 抑制剂时，将 2-取代的苯基喹啉-4-羧酸基团引入到 HDAC 抑制剂的帽基部分。总共合成了 30 种具有异羟肟酸或酰肼锌结合基团的化合物。在酶抑制试验中，活性化合物D28及其类似物D29对 HDAC1、2、3 和 6 表现出显着的 HDAC3 选择性。然而，与D28, 含酰肼化合物 (D29和D30) 具有显着提高的酶抑制活性在体外抗癌研究。进一步基于 K562 细胞的机制结果表明，诱导 G2/M 细胞周期停滞和促进细胞凋亡对分子的抗癌作用有重要贡献。D28. 总的来说，一种 HDAC3 选择性抑制剂（D28) 具有强大的体外抗癌活性被开发为治疗癌症的先导化合物。