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Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2
VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to b...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268560/ https://www.ncbi.nlm.nih.gov/pubmed/35807326 http://dx.doi.org/10.3390/molecules27134079 |
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author | Yousef, Reda G. Eldehna, Wagdy M. Elwan, Alaa Abdelaziz, Abdelaziz S. Mehany, Ahmed B. M. Gobaara, Ibraheem M. M. Alsfouk, Bshra A. Elkaeed, Eslam B. Metwaly, Ahmed M. Eissa, Ibrahim H. |
author_facet | Yousef, Reda G. Eldehna, Wagdy M. Elwan, Alaa Abdelaziz, Abdelaziz S. Mehany, Ahmed B. M. Gobaara, Ibraheem M. M. Alsfouk, Bshra A. Elkaeed, Eslam B. Metwaly, Ahmed M. Eissa, Ibrahim H. |
author_sort | Yousef, Reda G. |
collection | PubMed |
description | VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, (1)H-NMR, and (13)C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC(50) values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC(50) value of 77.02 nM (compare to sorafenib: IC(50) = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects. |
format | Online Article Text |
id | pubmed-9268560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92685602022-07-09 Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 Yousef, Reda G. Eldehna, Wagdy M. Elwan, Alaa Abdelaziz, Abdelaziz S. Mehany, Ahmed B. M. Gobaara, Ibraheem M. M. Alsfouk, Bshra A. Elkaeed, Eslam B. Metwaly, Ahmed M. Eissa, Ibrahim H. Molecules Article VEGFR-2, the subtype receptor tyrosine kinase (RTK) responsible for angiogenesis, is expressed in various cancer cells. Thus, VEGFER-2 inhibition is an efficient approach for the discovery of new anticancer agents. Accordingly, a new set of nicotinamide derivatives were designed and synthesized to be VEGFR-2 inhibitors. The chemical structures were confirmed using IR, (1)H-NMR, and (13)C-NMR spectroscopy. The obtained compounds were examined for their anti-proliferative activities against the human cancer cell lines (HCT-116 and HepG2). VEGFR-2 inhibitory activities were determined for the titled compounds. Compound 8 exhibited the strongest anti-proliferative activities with IC(50) values of 5.4 and 7.1 µM against HCT-116 and HepG2, respectively. Interestingly, compound 8 was the most potent VEGFR-2 inhibitor with an IC(50) value of 77.02 nM (compare to sorafenib: IC(50) = 53.65 nM). Treatment of HCT-116 cells with compound 8 produced arrest of the cell cycle at the G0–G1 phase and a total apoptosis increase from 3.05 to 19.82%—6.5-fold in comparison to the negative control. In addition, compound 8 caused significant increases in the expression levels of caspase-8 (9.4-fold) and Bax (9.2-fold), and a significant decrease in the Bcl-2 expression level (3-fold). The effects of compound 8 on the levels of the immunomodulatory proteins (TNF-α and IL-6) were examined. There was a marked decrease in the level of TNF-α (92.37%) compared to the control (82.47%) and a non-significant reduction in the level of IL-6. In silico docking, molecular dynamics simulations, and MM-PBSA studies revealed the high affinity, the correct binding, and the optimum dynamics of compound 8 inside the active site of VEGFR-2. Finally, in silico ADMET and toxicity studies indicated acceptable values of drug-likeness. In conclusion, compound 8 has emerged as a promising anti-proliferative agent targeting VEGFR-2 with significant apoptotic and immunomodulatory effects. MDPI 2022-06-24 /pmc/articles/PMC9268560/ /pubmed/35807326 http://dx.doi.org/10.3390/molecules27134079 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yousef, Reda G. Eldehna, Wagdy M. Elwan, Alaa Abdelaziz, Abdelaziz S. Mehany, Ahmed B. M. Gobaara, Ibraheem M. M. Alsfouk, Bshra A. Elkaeed, Eslam B. Metwaly, Ahmed M. Eissa, Ibrahim H. Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
title | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
title_full | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
title_fullStr | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
title_full_unstemmed | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
title_short | Design, Synthesis, In Silico and In Vitro Studies of New Immunomodulatory Anticancer Nicotinamide Derivatives Targeting VEGFR-2 |
title_sort | design, synthesis, in silico and in vitro studies of new immunomodulatory anticancer nicotinamide derivatives targeting vegfr-2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268560/ https://www.ncbi.nlm.nih.gov/pubmed/35807326 http://dx.doi.org/10.3390/molecules27134079 |
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