TY  - JOUR
AU  - Liang, Ting
AU  - Liu, Shiru
AU  - Dang, Baiyun
AU  - Luan, Xiaofa
AU  - Guo, Yifan
AU  - Steimbach, Raphael
AU  - Miller, Aubry
AU  - Hu, Jiadong
AU  - Lu, Long
AU  - Yue, Peiyu
AU  - Wang, Ruotian
AU  - Zheng, Meng
AU  - Gao, Jinming
AU  - Yin, Xia
AU  - Chen, Xin
TI  - Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.
JO  - European journal of medicinal chemistry
VL  - 275
SN  - 0009-4374
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2024-01367
SP  - 116624
PY  - 2024
AB  - 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.
KW  - Alzheimer's disease (Other)
KW  - HDAC6 inhibitor (Other)
KW  - Multimechanism (Other)
KW  - Selectivity (Other)
KW  - Tetrahydrocarboline (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38925015
DO  - DOI:10.1016/j.ejmech.2024.116624
UR  - https://inrepo02.dkfz.de/record/291284
ER  -