Wen Wen, Hu Jiadong, Wang Chenxi, Yang Rui, Zhang Yabo, Huang Baibei, Qiao Tingting, Wang Jiayun, Chen Xin
School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling 712100, PR China.
School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling 712100, PR China.
Bioorg Med Chem Lett. 2024 Apr 1;102:129670. doi: 10.1016/j.bmcl.2024.129670. Epub 2024 Feb 21.
Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro-β-carboline (THβC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC values. The most promising compound 11d preferentially inhibited HDAC6 (IC, 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner. In vitro, 11d induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of HO-induced oxidative stress.
组蛋白去乙酰化酶6（HDAC6）因其在阿尔茨海默病（AD）治疗中的潜在应用而受到越来越多的关注。合成了一系列带有芳基连接基的四氢-β-咔啉（THβC）异羟肟酸。在酶活性测定中，所有化合物均表现出纳摩尔级的IC值。最有前景的化合物11d优先抑制HDAC6（IC，8.64 nM），对HDAC1的选择性约为149倍。分子模拟表明，11d的异羟肟酸可以通过双齿螯合方式与锌离子结合。在体外，11d诱导PC12细胞的神经突生长而不产生毒性作用，并且在HO诱导的氧化应激模型中表现出明显的神经保护活性。
