Department of Medicinal Chemistry and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44, West Wenhua Road, 250012, Jinan, Shandong, PR China.
Department of Medicinal Chemistry and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44, West Wenhua Road, 250012, Jinan, Shandong, PR China.
Eur J Med Chem. 2021 Oct 5;221:113526. doi: 10.1016/j.ejmech.2021.113526. Epub 2021 May 7.
HDAC6 isoform selective inhibitors can be pursued as an alternative to pan-HDACs inhibitors due to their therapeutic effect and low toxicity. Efforts of the structure optimization of our previous compound 10c (IC = 4.4 nM) resulted in a new series of 3, 4-disubstituted-imidazolidine-2, 5-dione based HDAC6 inhibitors with better HDAC6 inhibitory activities and improved selectivities. The most potent compound 71 exhibited a low nanomolar HDAC6 inhibitory activity (IC = 2.1 nM) and showed 5545-fold, 5864-fold as well as 1638-fold selectivity relative to HDAC1, HDAC2 and HDAC8, respectively. Western blot analysis further confirmed that compound 71 selectively increased the acetylation level of α-tubulin without affecting histone H3. Moreover, compound 71 also possesses good properties in term of caspase-3 activation, apoptosis induction, anti-proliferative activity, cytotoxicity and plasma stability. Therefore, compound 71 can be applied in cancer therapy or used as a lead compound to develop more potent HDAC6 selective inhibitor.
由于其治疗效果和低毒性，HDAC6 同工型选择性抑制剂可以作为 pan-HDACs 抑制剂的替代品。我们对之前化合物 10c（IC = 4.4 nM）的结构进行优化的努力，得到了一系列新的基于 3,4-二取代-咪唑烷-2,5-二酮的 HDAC6 抑制剂，具有更好的 HDAC6 抑制活性和提高的选择性。最有效的化合物 71 表现出低纳摩尔级别的 HDAC6 抑制活性（IC = 2.1 nM），并且相对于 HDAC1、HDAC2 和 HDAC8，分别具有 5545 倍、5864 倍和 1638 倍的选择性。Western blot 分析进一步证实，化合物 71 选择性地增加了α-微管蛋白的乙酰化水平，而不影响组蛋白 H3。此外，化合物 71 在 caspase-3 激活、凋亡诱导、抗增殖活性、细胞毒性和血浆稳定性方面也具有良好的性质。因此，化合物 71 可应用于癌症治疗或用作开发更有效的 HDAC6 选择性抑制剂的先导化合物。
