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 (IC₅₀ = 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 (IC₅₀ = 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 异构体选择性抑制剂可以作为泛 HDAC 抑制剂的替代品。我们之前的化合物10c (IC ₅₀  = 4.4 nM)的结构优化努力产生了一系列新的基于 3, 4-二取代-咪唑烷-2, 5-二酮的 HDAC6 抑制剂，具有更好的 HDAC6 抑制活性和更高的选择性。最有效的化合物71表现出低纳摩尔 HDAC6 抑制活性 (IC ₅₀  = 2.1 nM)，并分别显示出相对于 HDAC1、HDAC2 和 HDAC8 的 5545 倍、5864 倍和 1638 倍的选择性。蛋白质印迹分析进一步证实化合物71选择性增加 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、细胞凋亡诱导、抗增殖活性、细胞毒性和血浆稳定性方面也具有良好的特性。因此，化合物71可应用于癌症治疗或作为先导化合物开发更有效的HDAC6选择性抑制剂。