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Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655065/ https://www.ncbi.nlm.nih.gov/pubmed/33161799 http://dx.doi.org/10.1080/14756366.2020.1839446 |
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author | Mehndiratta, Samir Chen, Mei-Chuan Chao, Yuh-Hsuan Lee, Cheng-Hsin Liou, Jing-Ping Lai, Mei-Jung Lee, Hsueh-Yun |
author_facet | Mehndiratta, Samir Chen, Mei-Chuan Chao, Yuh-Hsuan Lee, Cheng-Hsin Liou, Jing-Ping Lai, Mei-Jung Lee, Hsueh-Yun |
author_sort | Mehndiratta, Samir |
collection | PubMed |
description | 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 IC(50) 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 IC(50) 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. |
format | Online Article Text |
id | pubmed-7655065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-76550652020-11-19 Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms Mehndiratta, Samir Chen, Mei-Chuan Chao, Yuh-Hsuan Lee, Cheng-Hsin Liou, Jing-Ping Lai, Mei-Jung Lee, Hsueh-Yun J Enzyme Inhib Med Chem Research Paper 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 IC(50) 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 IC(50) 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. Taylor & Francis 2020-11-08 /pmc/articles/PMC7655065/ /pubmed/33161799 http://dx.doi.org/10.1080/14756366.2020.1839446 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Mehndiratta, Samir Chen, Mei-Chuan Chao, Yuh-Hsuan Lee, Cheng-Hsin Liou, Jing-Ping Lai, Mei-Jung Lee, Hsueh-Yun Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
title | Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
title_full | Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
title_fullStr | Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
title_full_unstemmed | Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
title_short | Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
title_sort | effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655065/ https://www.ncbi.nlm.nih.gov/pubmed/33161799 http://dx.doi.org/10.1080/14756366.2020.1839446 |
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