%0 Journal Article
%A Liang, Ting
%A Liu, Shiru
%A Dang, Baiyun
%A Luan, Xiaofa
%A Guo, Yifan
%A Steimbach, Raphael
%A Miller, Aubry
%A Hu, Jiadong
%A Lu, Long
%A Yue, Peiyu
%A Wang, Ruotian
%A Zheng, Meng
%A Gao, Jinming
%A Yin, Xia
%A Chen, Xin
%T Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.
%J European journal of medicinal chemistry
%V 275
%@ 0009-4374
%C Amsterdam [u.a.]
%I Elsevier Science
%M DKFZ-2024-01367
%P 116624
%D 2024
%X With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-β-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.
%K Alzheimer's disease (Other)
%K HDAC6 inhibitor (Other)
%K Multimechanism (Other)
%K Selectivity (Other)
%K Tetrahydrocarboline (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38925015
%R 10.1016/j.ejmech.2024.116624
%U https://inrepo02.dkfz.de/record/291284