Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784734674015223808
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
work_keys_str_mv AT abdelnabyranam invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT elmalahafafa invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT fakhreldeenrashar invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT saeedmarwam invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT nadeemraniai invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT younisnancys invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT abdelrahmanhanaam invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers
AT eldydamonynehadm invitroanticanceractivityscreeningofnovelfusedthiophenederivativesasvegfr2aktdualinhibitorsandapoptosisinducers