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Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further exa...

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Autores principales: Alsaif, Nawaf A., Taghour, Mohammed S., Alanazi, Mohammed M., Obaidullah, Ahmad J., Al-Mehizia, Abdulrahman A., Alanazi, Manal M., Aldawas, Saleh, Elwan, Alaa, Elkady, Hazem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168755/
https://www.ncbi.nlm.nih.gov/pubmed/34056992
http://dx.doi.org/10.1080/14756366.2021.1915303
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author Alsaif, Nawaf A.
Taghour, Mohammed S.
Alanazi, Mohammed M.
Obaidullah, Ahmad J.
Al-Mehizia, Abdulrahman A.
Alanazi, Manal M.
Aldawas, Saleh
Elwan, Alaa
Elkady, Hazem
author_facet Alsaif, Nawaf A.
Taghour, Mohammed S.
Alanazi, Mohammed M.
Obaidullah, Ahmad J.
Al-Mehizia, Abdulrahman A.
Alanazi, Manal M.
Aldawas, Saleh
Elwan, Alaa
Elkady, Hazem
author_sort Alsaif, Nawaf A.
collection PubMed
description Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC(50) values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC(50) values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC(50) = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).
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spelling pubmed-81687552021-06-07 Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers Alsaif, Nawaf A. Taghour, Mohammed S. Alanazi, Mohammed M. Obaidullah, Ahmad J. Al-Mehizia, Abdulrahman A. Alanazi, Manal M. Aldawas, Saleh Elwan, Alaa Elkady, Hazem J Enzyme Inhib Med Chem Research Paper Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC(50) values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC(50) values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC(50) = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold). Taylor & Francis 2021-05-31 /pmc/articles/PMC8168755/ /pubmed/34056992 http://dx.doi.org/10.1080/14756366.2021.1915303 Text en © 2021 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
Alsaif, Nawaf A.
Taghour, Mohammed S.
Alanazi, Mohammed M.
Obaidullah, Ahmad J.
Al-Mehizia, Abdulrahman A.
Alanazi, Manal M.
Aldawas, Saleh
Elwan, Alaa
Elkady, Hazem
Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
title Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
title_full Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
title_fullStr Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
title_full_unstemmed Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
title_short Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
title_sort discovery of new vegfr-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168755/
https://www.ncbi.nlm.nih.gov/pubmed/34056992
http://dx.doi.org/10.1080/14756366.2021.1915303
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