Zinc-dependent histone deacetylases (HDACs) are important epigenetic regulators that have become important drug targets for treating cancer. Although five HDAC inhibitors have been approved for treating several cancers, there is still a huge demand on discovering new HDAC inhibitors to explore the therapeutic potentials for treating solid tumor cancers. Substrate mimics are a powerful rational design approach for the development of potent inhibitors. Here we describe the rational design, synthesis, biological evaluation, molecular docking and in vivo efficacy study of a class of HDAC inhibitors using N^ε-acetyl lysine mimics that are derived from cysteine. As a result, compounds 7a, 9b and 13d demonstrated pan-HDAC inhibition and broad cytotoxicity against several cancer cell lines, comparable to the approved HDAC inhibitor SAHA. Furthermore, 13d significantly inhibited tumor growth in a A549 xenograft mice model without any obvious weight loss, supporting that the cysteine-derived acetyl lysine mimics are promising HDAC inhibitors with therapeutic potentials for treating cancer.

锌依赖性组蛋白脱乙酰酶 (HDACs) 是重要的表观遗传调节因子，已成为治疗癌症的重要药物靶点。尽管有五种 HDAC 抑制剂已被批准用于治疗多种癌症，但仍需要发现新的 HDAC 抑制剂以探索治疗实体瘤癌症的治疗潜力。底物模拟物是一种强大的合理设计方法，用于开发有效的抑制剂。在这里，我们描述了使用衍生自半胱氨酸的N ^ε -乙酰赖氨酸模拟物对一类 HDAC 抑制剂的合理设计、合成、生物学评估、分子对接和体内功效研究。结果，化合物7a、9b和13d证明了对几种癌细胞系的泛HDAC抑制和广泛的细胞毒性，与批准的HDAC抑制剂SAHA相当。此外，13d在 A549 异种移植小鼠模型中显着抑制肿瘤生长而没有任何明显的体重减轻，这支持了半胱氨酸衍生的乙酰赖氨酸模拟物是具有治疗癌症潜力的有前景的 HDAC 抑制剂。