Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms

Samir Mehndiratta; Mei Chuan Chen; Yuh Hsuan Chao; Cheng Hsin Lee; Jing Ping Liou; Mei Jung Lai; Hsueh Yun Lee

doi:10.1080/14756366.2020.1839446

Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms

Samir Mehndiratta, Mei Chuan Chen, Yuh Hsuan Chao, Cheng Hsin Lee, Jing Ping Liou, Mei Jung Lai, Hsueh Yun Lee

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC₅₀ values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC₅₀ values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.

Original language	English
Pages (from-to)	74-84
Number of pages	11
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	36
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2020.1839446
Publication status	Published - Jan 1 2021

Keywords

acrylamide
colon cancer
HDAC
hydroxamic acid
lung cancer
Quinoline

ASJC Scopus subject areas

Pharmacology
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/14756366.2020.1839446

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title = "Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms",

abstract = "A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.",

keywords = "acrylamide, colon cancer, HDAC, hydroxamic acid, lung cancer, Quinoline",

author = "Samir Mehndiratta and Chen, {Mei Chuan} and Chao, {Yuh Hsuan} and Lee, {Cheng Hsin} and Liou, {Jing Ping} and Lai, {Mei Jung} and Lee, {Hsueh Yun}",

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AU - Lee, Cheng Hsin

AU - Liou, Jing Ping

AU - Lai, Mei Jung

AU - Lee, Hsueh Yun

N1 - Funding Information: This research was supported by the Ministry of Science and Technology, Taiwan [grant no. MOST108-2320-B-038?042-MY3]. Publisher Copyright: © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.

AB - A series of 3-subsituted quinolinehydroxamic acids has been synthesised and evaluated for their effect on human lung cancer cell line (A549), human colorectal cancer cell line (HCT116) and HDAC isoforms 1, 2, 6, and 8. The results indicated that substitution at C3 of quinoline is favoured for HDAC6 selectivity. Two compounds (25 and 26) were also found to be potent anti-proliferative compounds with IC50 values ranging from 1.29 to 2.13 µM against A549 and HCT116 cells. These compounds displayed remarkable selectivity for HDAC6 over other HDAC isoforms with nanomolar IC50 values. Western blot analysis revealed that compounds of this series activate apoptotic caspase pathway as indicated by cleavage of caspase 3, 8, and 9 and also increase phosphorylated H2AX thus inducing DNA double strand fragmentation in a concentration dependent manner. Flow cytometric analysis also displayed a dose dependent increase of cell population in sub G1 phase.

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Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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