1. Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities.
- Author
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Wen W, Hu J, Wang C, Yang R, Zhang Y, Huang B, Qiao T, Wang J, and Chen X
- Subjects
- Rats, Animals, Histone Deacetylase 6, Hydroxamic Acids pharmacology, Neuronal Outgrowth, Histone Deacetylase 1 metabolism, Structure-Activity Relationship, Histone Deacetylase Inhibitors pharmacology, Hydrogen Peroxide pharmacology, Carbolines
- Abstract
Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro-β-carboline (THβC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC
50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC50 , 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner. In vitro, 11d induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of H2 O2 -induced oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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