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Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma
Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209864/ https://www.ncbi.nlm.nih.gov/pubmed/30360426 http://dx.doi.org/10.3390/cells7100177 |
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author | Chung, Po Yee Lam, Pik Ling Zhou, Yuanyuan Gasparello, Jessica Finotti, Alessia Chilin, Adriana Marzaro, Giovanni Gambari, Roberto Bian, Zhaoxiang Kwok, Wai Ming Wong, Wai Yeung Wang, Xi Lam, Alfred King-yin Chan, Albert Sun-chi Li, Xingshu Ma, Jessica Yuen Wuen Chui, Chung Hin Lam, Kim Hung Tang, Johnny Cheuk On |
author_facet | Chung, Po Yee Lam, Pik Ling Zhou, Yuanyuan Gasparello, Jessica Finotti, Alessia Chilin, Adriana Marzaro, Giovanni Gambari, Roberto Bian, Zhaoxiang Kwok, Wai Ming Wong, Wai Yeung Wang, Xi Lam, Alfred King-yin Chan, Albert Sun-chi Li, Xingshu Ma, Jessica Yuen Wuen Chui, Chung Hin Lam, Kim Hung Tang, Johnny Cheuk On |
author_sort | Chung, Po Yee |
collection | PubMed |
description | Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma. |
format | Online Article Text |
id | pubmed-6209864 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62098642018-11-02 Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma Chung, Po Yee Lam, Pik Ling Zhou, Yuanyuan Gasparello, Jessica Finotti, Alessia Chilin, Adriana Marzaro, Giovanni Gambari, Roberto Bian, Zhaoxiang Kwok, Wai Ming Wong, Wai Yeung Wang, Xi Lam, Alfred King-yin Chan, Albert Sun-chi Li, Xingshu Ma, Jessica Yuen Wuen Chui, Chung Hin Lam, Kim Hung Tang, Johnny Cheuk On Cells Brief Report Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma. MDPI 2018-10-22 /pmc/articles/PMC6209864/ /pubmed/30360426 http://dx.doi.org/10.3390/cells7100177 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Brief Report Chung, Po Yee Lam, Pik Ling Zhou, Yuanyuan Gasparello, Jessica Finotti, Alessia Chilin, Adriana Marzaro, Giovanni Gambari, Roberto Bian, Zhaoxiang Kwok, Wai Ming Wong, Wai Yeung Wang, Xi Lam, Alfred King-yin Chan, Albert Sun-chi Li, Xingshu Ma, Jessica Yuen Wuen Chui, Chung Hin Lam, Kim Hung Tang, Johnny Cheuk On Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma |
title | Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma |
title_full | Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma |
title_fullStr | Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma |
title_full_unstemmed | Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma |
title_short | Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma |
title_sort | targeting dna binding for nf-κb as an anticancer approach in hepatocellular carcinoma |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209864/ https://www.ncbi.nlm.nih.gov/pubmed/30360426 http://dx.doi.org/10.3390/cells7100177 |
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