Liang Tao, Hou Xuben, Zhou Yi, Yang Xinying, Fang Hao
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, P. R. China.
ACS Med Chem Lett. 2019 Jul 5;10(8):1122-1127. doi: 10.1021/acsmedchemlett.9b00084. eCollection 2019 Aug 8.
Histone deacetylase 6 (HDAC6) has emerged as a promising drug target for various human diseases, including diverse neurodegenerative diseases and cancer. Herein, we reported a series of 2,4-imidazolinedione derivatives as novel HDAC6 isoform-selective inhibitors based on structure-based drug design. Most target compounds exhibit good profiles in a preliminary screening concerning HDAC6 inhibitory activities. Moreover, the most active compound increases the acetylation level of α-tubulin with little effect on the acetylation of histone H3. Further biological evaluation suggested that potent compound , which possesses good antiproliferative activity, could induce apoptosis in HL-60 cell by activating caspase 3.
组蛋白去乙酰化酶6（HDAC6）已成为包括多种神经退行性疾病和癌症在内的各种人类疾病的一个有前景的药物靶点。在此，我们基于结构药物设计报道了一系列2,4-咪唑啉二酮衍生物作为新型HDAC6亚型选择性抑制剂。大多数目标化合物在关于HDAC6抑制活性的初步筛选中表现出良好的特性。此外，活性最强的化合物提高了α-微管蛋白的乙酰化水平，而对组蛋白H3的乙酰化影响很小。进一步的生物学评估表明，具有良好抗增殖活性的强效化合物可通过激活半胱天冬酶3诱导HL-60细胞凋亡。
