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New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation

BACKGROUND: Cancer is still a major world health threat, causing a high rate of mortality. VEGFR-2 inhibitor anticancer agents are of great significance. However, they showed some serious side effects. PURPOSE: To discover new effective and safer anticancer agents, a new series of piperazinylquinoxa...

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Autores principales: Abdallah, Abdallah E, Mabrouk, Reda R, Elnagar, Mohamed R, Farrag, Amel Mostafa, Kalaba, Mohamed H, Sharaf, Mohamed H, El-Fakharany, Esmail M, Bakhotmah, Dina Abed, Elkaeed, Eslam B, Al Ward, Maged Mohammed Saleh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904266/
https://www.ncbi.nlm.nih.gov/pubmed/35281317
http://dx.doi.org/10.2147/DDDT.S344750
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author Abdallah, Abdallah E
Mabrouk, Reda R
Elnagar, Mohamed R
Farrag, Amel Mostafa
Kalaba, Mohamed H
Sharaf, Mohamed H
El-Fakharany, Esmail M
Bakhotmah, Dina Abed
Elkaeed, Eslam B
Al Ward, Maged Mohammed Saleh
author_facet Abdallah, Abdallah E
Mabrouk, Reda R
Elnagar, Mohamed R
Farrag, Amel Mostafa
Kalaba, Mohamed H
Sharaf, Mohamed H
El-Fakharany, Esmail M
Bakhotmah, Dina Abed
Elkaeed, Eslam B
Al Ward, Maged Mohammed Saleh
author_sort Abdallah, Abdallah E
collection PubMed
description BACKGROUND: Cancer is still a major world health threat, causing a high rate of mortality. VEGFR-2 inhibitor anticancer agents are of great significance. However, they showed some serious side effects. PURPOSE: To discover new effective and safer anticancer agents, a new series of piperazinylquinoxaline-based derivatives was designed and synthesized on the basis of the pharmacophoric features of VEGFR-2 inhibitor drugs. METHODS: The new candidates were evaluated against A549 lung cancer cells, HepG-2 hepatoma cells, Caco-2 colon cancer cells, MDA breast cancer cells, and VEGFR-2 kinase. Moreover, cell cycle kinetics and apoptosis rates were studied in HepG-2 cells treated with compound 11, which was the most promising candidate. RESULTS: The new derivatives revealed better antitumor results (IC(50) from 6.48 to 38.58 µM) against the aforementioned cancer cell lines than sorafenib. Also, the new candidates showed VEGFR-2 inhibition with IC(50) values ranging from 0.19 to 0.60 µM compared to 0.08 µM for sorafenib. Compound 11, meanwhile, showed IC(50) values equal to 10.61, 9.52, 12.45, 11.52, and 0.19 µM against the cancer cell lines and VEGFR-2, respectively. Moreover, compound 11 raised the apoptosis rate in HepG-2 cells from 5% to 44% and caused 4, 2.3, and 3-fold increases in BAX/Bcl-2 ratio, caspase-3 level, and P53 expression, respectively, compared to control untreated cells. Finally, the new derivatives displayed the correct binding mode into VEGFR-2 kinase pocket, giving interactions with the essential residues. CONCLUSION: This work suggests that compound 11 is a very significant anticancer candidate, and piperazinylquinoxaline is an important scaffold in the development of new potential effective and safer VEGFR-2 inhibitor agents.
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spelling pubmed-89042662022-03-10 New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation Abdallah, Abdallah E Mabrouk, Reda R Elnagar, Mohamed R Farrag, Amel Mostafa Kalaba, Mohamed H Sharaf, Mohamed H El-Fakharany, Esmail M Bakhotmah, Dina Abed Elkaeed, Eslam B Al Ward, Maged Mohammed Saleh Drug Des Devel Ther Original Research BACKGROUND: Cancer is still a major world health threat, causing a high rate of mortality. VEGFR-2 inhibitor anticancer agents are of great significance. However, they showed some serious side effects. PURPOSE: To discover new effective and safer anticancer agents, a new series of piperazinylquinoxaline-based derivatives was designed and synthesized on the basis of the pharmacophoric features of VEGFR-2 inhibitor drugs. METHODS: The new candidates were evaluated against A549 lung cancer cells, HepG-2 hepatoma cells, Caco-2 colon cancer cells, MDA breast cancer cells, and VEGFR-2 kinase. Moreover, cell cycle kinetics and apoptosis rates were studied in HepG-2 cells treated with compound 11, which was the most promising candidate. RESULTS: The new derivatives revealed better antitumor results (IC(50) from 6.48 to 38.58 µM) against the aforementioned cancer cell lines than sorafenib. Also, the new candidates showed VEGFR-2 inhibition with IC(50) values ranging from 0.19 to 0.60 µM compared to 0.08 µM for sorafenib. Compound 11, meanwhile, showed IC(50) values equal to 10.61, 9.52, 12.45, 11.52, and 0.19 µM against the cancer cell lines and VEGFR-2, respectively. Moreover, compound 11 raised the apoptosis rate in HepG-2 cells from 5% to 44% and caused 4, 2.3, and 3-fold increases in BAX/Bcl-2 ratio, caspase-3 level, and P53 expression, respectively, compared to control untreated cells. Finally, the new derivatives displayed the correct binding mode into VEGFR-2 kinase pocket, giving interactions with the essential residues. CONCLUSION: This work suggests that compound 11 is a very significant anticancer candidate, and piperazinylquinoxaline is an important scaffold in the development of new potential effective and safer VEGFR-2 inhibitor agents. Dove 2022-03-03 /pmc/articles/PMC8904266/ /pubmed/35281317 http://dx.doi.org/10.2147/DDDT.S344750 Text en © 2022 Abdallah et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Abdallah, Abdallah E
Mabrouk, Reda R
Elnagar, Mohamed R
Farrag, Amel Mostafa
Kalaba, Mohamed H
Sharaf, Mohamed H
El-Fakharany, Esmail M
Bakhotmah, Dina Abed
Elkaeed, Eslam B
Al Ward, Maged Mohammed Saleh
New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
title New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
title_full New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
title_fullStr New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
title_full_unstemmed New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
title_short New Series of VEGFR-2 Inhibitors and Apoptosis Enhancers: Design, Synthesis and Biological Evaluation
title_sort new series of vegfr-2 inhibitors and apoptosis enhancers: design, synthesis and biological evaluation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904266/
https://www.ncbi.nlm.nih.gov/pubmed/35281317
http://dx.doi.org/10.2147/DDDT.S344750
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