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

Research output: Contribution to journal › Article

15 Citations (Scopus)

Abstract

This paper reports the development of a series of 5-aroylindolyl-substitued 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 IC50 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
Journal	Journal of Medicinal Chemistry
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00151
Publication status	Accepted/In press - Jan 29 2018

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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5-Aroylindoles Act as Selective Histone Deacetylase 6 Inhibitors Ameliorating Alzheimer's Disease Phenotypes. / Lee, Hsueh Yun; Fan, Sheng Jun; Huang, Fang I.; Chao, Hsin Yi; Hsu, Kai Cheng; Lin, Tony Eight; Yeh, Teng Kuang; Lai, Mei Jung; Li, Yu Hsuan; Huang, Hsiang Ling; Yang, Chia Ron; Liou, Jing Ping.

In: Journal of Medicinal Chemistry, 29.01.2018.

Research output: Contribution to journal › Article

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abstract = "This paper reports the development of a series of 5-aroylindolyl-substitued 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 IC50 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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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

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AB - This paper reports the development of a series of 5-aroylindolyl-substitued 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 IC50 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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