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In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers
Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffol...
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/PMC9229165/ https://www.ncbi.nlm.nih.gov/pubmed/35745619 http://dx.doi.org/10.3390/ph15060700 |
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author | Abdelnaby, Rana M. El-Malah, Afaf A. FakhrEldeen, Rasha R. Saeed, Marwa M. Nadeem, Rania I. Younis, Nancy S. Abdel-Rahman, Hanaa M. El-Dydamony, Nehad M. |
author_facet | Abdelnaby, Rana M. El-Malah, Afaf A. FakhrEldeen, Rasha R. Saeed, Marwa M. Nadeem, Rania I. Younis, Nancy S. Abdel-Rahman, Hanaa M. El-Dydamony, Nehad M. |
author_sort | Abdelnaby, Rana M. |
collection | PubMed |
description | Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC(50) = 3.105 and 2.15 μM) and 4c (IC(50) = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC(50) = 0.075 and 4.60 μM, respectively, while 3b showed IC(50) = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma. |
format | Online Article Text |
id | pubmed-9229165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92291652022-06-25 In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers Abdelnaby, Rana M. El-Malah, Afaf A. FakhrEldeen, Rasha R. Saeed, Marwa M. Nadeem, Rania I. Younis, Nancy S. Abdel-Rahman, Hanaa M. El-Dydamony, Nehad M. Pharmaceuticals (Basel) Article Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC(50) = 3.105 and 2.15 μM) and 4c (IC(50) = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC(50) = 0.075 and 4.60 μM, respectively, while 3b showed IC(50) = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma. MDPI 2022-06-02 /pmc/articles/PMC9229165/ /pubmed/35745619 http://dx.doi.org/10.3390/ph15060700 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 Abdelnaby, Rana M. El-Malah, Afaf A. FakhrEldeen, Rasha R. Saeed, Marwa M. Nadeem, Rania I. Younis, Nancy S. Abdel-Rahman, Hanaa M. El-Dydamony, Nehad M. In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers |
title | In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers |
title_full | In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers |
title_fullStr | In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers |
title_full_unstemmed | In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers |
title_short | In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers |
title_sort | in vitro anticancer activity screening of novel fused thiophene derivatives as vegfr-2/akt dual inhibitors and apoptosis inducers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229165/ https://www.ncbi.nlm.nih.gov/pubmed/35745619 http://dx.doi.org/10.3390/ph15060700 |
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