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Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease

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 s...

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Main Authors: Liang, Ting (Author) , Liu, Shiru (Author) , Dang, Baiyun (Author) , Luan, Xiaofa (Author) , Guo, Yifan (Author) , Steimbach, Raphael R. (Author) , Hu, Jiadong (Author) , Lu, Long (Author) , Yue, Peiyu (Author) , Wang, Ruotian (Author) , Zheng, Meng (Author) , Gao, Jinming (Author) , Yin, Xia (Author) , Chen, Xin (Author)
Format: Article (Journal)
Language:English
Published: 5 September 2024
In: European journal of medicinal chemistry
Year: 2024, Volume: 275, Pages: 1-18
ISSN:1768-3254
DOI:10.1016/j.ejmech.2024.116624
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejmech.2024.116624
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S022352342400504X
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Author Notes:Ting Liang, Shiru Liu, Baiyun Dang, Xiaofa Luan, Yifan Guo, Raphael R. Steimbach, Jiadong Hu, Long Lu, Peiyu Yue, Ruotian Wang, Meng Zheng, Jinming Gao, Xia Yin, Xin Chen
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Summary: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.
Item Description:Online verfügbar 24 June 2024, Version des Artikel 25 June 2024
Gesehen am 08.01.2025
Physical Description:Online Resource
ISSN:1768-3254
DOI:10.1016/j.ejmech.2024.116624

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