Liang Ting, Xie Zhao, Dang Baiyun, Wang Jiayun, Zhang Tongtong, Luan Xiaofa, Lu Tao, Cao Chenyu, Chen Xin
Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
Bioorg Med Chem Lett. 2023 Feb 1;81:129148. doi: 10.1016/j.bmcl.2023.129148. Epub 2023 Jan 21.
Novel indole-piperazine derivatives with a hydroxamic acid moiety were designed and synthesized as selective histone deacetylase 6 (HDAC6) inhibitors. In enzymatic assays, all compounds exhibited nanomolar IC values. N-hydroxy-4-((4-(7-methyl-1H-indole-3-carbonyl)piperazin-1-yl)methyl)benzamide, 9c, was the most potent HDAC6 inhibitor (IC, 13.6 nM). In vitro, 9c induced neurite outgrowth of PC12 cells without producing toxic effects, better than Tubastatin A (Tub A). Additionally, 9c demonstrated blatant neuroprotective activity in PC12 cells against HO-induced oxidative damage. In western blot assay, 9c could increase the acetylation of α-tubulin in a dose-dependent manner.
设计并合成了具有异羟肟酸部分的新型吲哚 - 哌嗪衍生物作为选择性组蛋白去乙酰化酶6（HDAC6）抑制剂。在酶促试验中，所有化合物均表现出纳摩尔级的IC值。N - 羟基 - 4 - （（4 - （7 - 甲基 - 1H - 吲哚 - 3 - 羰基）哌嗪 - 1 - 基）甲基）苯甲酰胺（9c）是最有效的HDAC6抑制剂（IC，13.6 nM）。在体外，9c可诱导PC12细胞的神经突生长且不产生毒性作用，效果优于曲古抑菌素A（Tub A）。此外，9c在PC12细胞中对过氧化氢诱导的氧化损伤表现出明显的神经保护活性。在蛋白质免疫印迹试验中，9c可呈剂量依赖性地增加α - 微管蛋白的乙酰化水平。
