Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors

作者：Chen, Chen; Hou, Xuben; Wang, Guohua; Pan, Wenyan; Yang, Xinying; Zhang, Yingkai; Fang, Hao^*

来源：European Journal of Medicinal Chemistry, 2017, 133: 11-23.

DOI：10.1016/j.ejmech.2017.03.064

• Quinoline
• Hydroxamic acid
• Class I HDACs
• Anti-proliferative
• Class I celluar activity
• Pro-apoptosis activity

Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity. In terms of HDAC isoforms selectivity, compounds 4a exhibited preferable inhibition for class I HDACs, especially for HDAC8, the IC50 value (442 nM) was much lower than that of Vorinostat (7468 nM). Subsequently, we performed class I & Ha HDACs whole cell enzyme assay to evaluate inhibitory activity in whole cell context. Compounds 4a and 4e displayed much better cellular activity for class I HDACs than that for class Ha HDACs, which indicated that 4a and 4e might be potent class I HDAC inhibitors. Meanwhile, flow cytometry analysis showed that compound 4a and 4e can promote cell apoptosis in vitro.

• 出版日期2017-6-16
• 单位山东大学