%0 Journal Article
%T Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.
%A Liang T
%A Liu S
%A Dang B
%A Luan X
%A Guo Y
%A Steimbach RR
%A Hu J
%A Lu L
%A Yue P
%A Wang R
%A Zheng M
%A Gao J
%A Yin X
%A Chen X
%J Eur J Med Chem
%V 275
%N 0
%D 2024 Sep 5
%M 38925015
%F 7.088
%R 10.1016/j.ejmech.2024.116624
%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.