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Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers
Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives were designed and synthesized based on an N-(ethyl benzoate) moiety. The structure of the designed derivatives was confirm...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069231/ https://www.ncbi.nlm.nih.gov/pubmed/37020892 http://dx.doi.org/10.1039/d3ra00887h |
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author | Raslan, Reham R. Ammar, Yousry A. Fouad, Sawsan A. Hessein, Sadia A. Shmiess, Nadia A. M. Ragab, Ahmed |
author_facet | Raslan, Reham R. Ammar, Yousry A. Fouad, Sawsan A. Hessein, Sadia A. Shmiess, Nadia A. M. Ragab, Ahmed |
author_sort | Raslan, Reham R. |
collection | PubMed |
description | Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives were designed and synthesized based on an N-(ethyl benzoate) moiety. The structure of the designed derivatives was confirmed by different spectroscopic techniques (FT-IR and NMR) and elemental analysis and then evaluated as antiproliferative against HepG-2 and Caco-2 cell lines compared with Doxorubicin. The spiro-pyridine derivatives 5, 7, and 8 exhibited a remarkably higher activity against Caco-2 cell lines than that of other derivatives. Additionally, these derivatives exhibited activation in the Bax and suppressed Bcl-2 expression with variable degrees. Interestingly, compound 7 showed the lowest cytotoxicity value on Caco-2 cells (IC(50) = 7.83 ± 0.50 μM) compared with Doxorubicin (IC(50) = 12.49 ± 1.10 μM). Additionally, this compound showed activation of the Bax gene (7.508-fold) and suppressed Bcl-2 (0.194-fold) compared to untreated Caco-2 cells, as revealed by the qRT-PCR technique. Moreover, compound 7 could inhibit EGFR and VEGFR-2 with sub-micromole values of 0.124 μM and 0.221 μM compared with Erlotinib (IC(50) = 0.033 μM) and Sorafenib (IC(50) = 0.043 μM), respectively. Further, cell cycle and apoptosis analysis demonstrated that compound 7 promoted apoptosis by increasing the apoptosis rate from 1.92 to 42.35% and the S cell accumulation ratio from 31.18 to 42.07% compared to untreated Caco-2 cells. Finally, the most active compound 7 showed good drug-likeness and toxicity profiles. Besides, molecular docking studies were performed to determine the binding mode, which is in agreement with the in vitro results. |
format | Online Article Text |
id | pubmed-10069231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-100692312023-04-04 Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers Raslan, Reham R. Ammar, Yousry A. Fouad, Sawsan A. Hessein, Sadia A. Shmiess, Nadia A. M. Ragab, Ahmed RSC Adv Chemistry Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives were designed and synthesized based on an N-(ethyl benzoate) moiety. The structure of the designed derivatives was confirmed by different spectroscopic techniques (FT-IR and NMR) and elemental analysis and then evaluated as antiproliferative against HepG-2 and Caco-2 cell lines compared with Doxorubicin. The spiro-pyridine derivatives 5, 7, and 8 exhibited a remarkably higher activity against Caco-2 cell lines than that of other derivatives. Additionally, these derivatives exhibited activation in the Bax and suppressed Bcl-2 expression with variable degrees. Interestingly, compound 7 showed the lowest cytotoxicity value on Caco-2 cells (IC(50) = 7.83 ± 0.50 μM) compared with Doxorubicin (IC(50) = 12.49 ± 1.10 μM). Additionally, this compound showed activation of the Bax gene (7.508-fold) and suppressed Bcl-2 (0.194-fold) compared to untreated Caco-2 cells, as revealed by the qRT-PCR technique. Moreover, compound 7 could inhibit EGFR and VEGFR-2 with sub-micromole values of 0.124 μM and 0.221 μM compared with Erlotinib (IC(50) = 0.033 μM) and Sorafenib (IC(50) = 0.043 μM), respectively. Further, cell cycle and apoptosis analysis demonstrated that compound 7 promoted apoptosis by increasing the apoptosis rate from 1.92 to 42.35% and the S cell accumulation ratio from 31.18 to 42.07% compared to untreated Caco-2 cells. Finally, the most active compound 7 showed good drug-likeness and toxicity profiles. Besides, molecular docking studies were performed to determine the binding mode, which is in agreement with the in vitro results. The Royal Society of Chemistry 2023-04-03 /pmc/articles/PMC10069231/ /pubmed/37020892 http://dx.doi.org/10.1039/d3ra00887h Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Raslan, Reham R. Ammar, Yousry A. Fouad, Sawsan A. Hessein, Sadia A. Shmiess, Nadia A. M. Ragab, Ahmed Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers |
title | Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers |
title_full | Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers |
title_fullStr | Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers |
title_full_unstemmed | Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers |
title_short | Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFR(Wt) and VEGFR-2 inhibitors with apoptotic inducers |
title_sort | evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′h-spiro-pyridine derivatives as a new class of egfr(wt) and vegfr-2 inhibitors with apoptotic inducers |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069231/ https://www.ncbi.nlm.nih.gov/pubmed/37020892 http://dx.doi.org/10.1039/d3ra00887h |
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