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

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

  • Eur J Med Chem. 2024 Sep 5:275:116624. doi: 10.1016/j.ejmech.2024.116624.
Ting Liang 1,  Shiru Liu 1,  Baiyun Dang 1,  Xiaofa Luan 1,  Yifan Guo 1,  Raphael R Steimbach 2,  Jiadong Hu 3,  Long Lu 3,  Peiyu Yue 3,  Ruotian Wang 3,  Meng Zheng 1,  Jinming Gao 4,  Xia Yin 5,  Xin Chen 6
Affiliations

Affiliations

  • 1 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
  • 2 Cancer Drug Development Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany; Biosciences Faculty, University of Heidelberg, 69120, Heidelberg, Germany.
  • 3 School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling, 712100, PR China.
  • 4 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China. Electronic address: jinminggao@nwafu.edu.cn.
  • 5 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China. Electronic address: yinxiabb@outlook.com.
  • 6 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China. Electronic address: chenxin1888@nwsuaf.edu.cn.
PMID: 38925015 DOI: 10.1016/j.ejmech.2024.116624
Abstract

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.

Keywords

Alzheimer's disease; HDAC6 inhibitor; Multimechanism; Selectivity; Tetrahydrocarboline.

Figures
Products