Multimechanism biological profiling of tetrahydro-ß-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.
Eur J Med Chem
; 275: 116624, 2024 Sep 05.
Article
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| MEDLINE
| ID: mdl-38925015
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-ß-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.
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MEDLINE
Asunto principal:
Pez Cebra
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Carbolinas
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Fármacos Neuroprotectores
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Inhibidores de Histona Desacetilasas
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Enfermedad de Alzheimer
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Histona Desacetilasa 6
Idioma:
En
Revista:
Eur J Med Chem
Año:
2024
Tipo del documento:
Article