5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes

Hsueh Yun Lee; Sheng Jun Fan; Fang I. Huang; Hsin Yi Chao; Kai Cheng Hsu; Tony Eight Lin; Teng Kuang Yeh; Mei Jung Lai; Yu Hsuan Li; Hsiang Ling Huang; Chia Ron Yang; Jing Ping Liou

doi:10.1021/acs.jmedchem.8b00151

5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes

Hsueh Yun Lee, Sheng Jun Fan, Fang I. Huang, Hsin Yi Chao, Kai Cheng Hsu, Tony Eight Lin, Teng Kuang Yeh, Mei Jung Lai, Yu Hsuan Li, Hsiang Ling Huang, Chia Ron Yang, Jing Ping Liou

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58 Citations (Scopus)

Abstract

This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC ₅₀ value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.

Original language	English
Pages (from-to)	7087-7102
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	16
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00151
Publication status	Published - Aug 23 2018

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes",

abstract = "This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC 50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future. ",

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doi = "10.1021/acs.jmedchem.8b00151",

language = "English",

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T1 - 5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes

AU - Lee, Hsueh Yun

AU - Fan, Sheng Jun

AU - Huang, Fang I.

AU - Chao, Hsin Yi

AU - Hsu, Kai Cheng

AU - Lin, Tony Eight

AU - Yeh, Teng Kuang

AU - Lai, Mei Jung

AU - Li, Yu Hsuan

AU - Huang, Hsiang Ling

AU - Yang, Chia Ron

AU - Liou, Jing Ping

PY - 2018/8/23

Y1 - 2018/8/23

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AB - This paper reports the development of a series of 5-aroylindolyl-substituted hydroxamic acids. N-Hydroxy-4-((5-(4-methoxybenzoyl)-1H-indol-1-yl)methyl)benzamide (6) has potent inhibitory selectivity against histone deacetylase 6 (HDAC6) with an IC 50 value of 3.92 nM. It decreases not only the level of phosphorylation of tau proteins but also the aggregation of tau proteins. Compound 6 also shows neuroprotective activity by triggering ubiquitination. In animal models, compound 6 is able to ameliorate the impaired learning and memory, and it crosses the blood-brain barrier after oral administration. Compound 6 can be developed as a potential treatment for Alzheimer's disease in the future.

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ER -

5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes

Abstract

ASJC Scopus subject areas

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