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Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation

Multitarget anticancer drugs are more superior than single target drugs regarding patient compliance, drug adverse effects, drug-drug interactions, drug resistance as well as pharmaceutical industry economics. Dysregulation of both VEGFR-2 and c-Met tyrosine kinases (TKs) could result in development...

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Autores principales: Hassan, Abdelfattah, Mosallam, Ahmed M., Ibrahim, Amal O. A., Badr, Mohamed, Abdelmonsef, Aboubakr H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616113/
https://www.ncbi.nlm.nih.gov/pubmed/37903949
http://dx.doi.org/10.1038/s41598-023-45687-y
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author Hassan, Abdelfattah
Mosallam, Ahmed M.
Ibrahim, Amal O. A.
Badr, Mohamed
Abdelmonsef, Aboubakr H.
author_facet Hassan, Abdelfattah
Mosallam, Ahmed M.
Ibrahim, Amal O. A.
Badr, Mohamed
Abdelmonsef, Aboubakr H.
author_sort Hassan, Abdelfattah
collection PubMed
description Multitarget anticancer drugs are more superior than single target drugs regarding patient compliance, drug adverse effects, drug-drug interactions, drug resistance as well as pharmaceutical industry economics. Dysregulation of both VEGFR-2 and c-Met tyrosine kinases (TKs) could result in development and progression of different human cancers. Herein, we reported a novel series of 3-phenylquinazolin-2,4(1H,3H)-diones with thiourea moiety as dual VEGFR-2/c-Met TKs. Compared to sorafenib, cabozantinib went behind VEGFR-2 inhibition to target c-Met TK. The dual VEGFR-2/c-Met inhibitory activity of cabozantinib is due to a longer HB domain than that of sorafenib. Based on pharmacophore of cabozantinib analogues, we designed new dual VEGFR-2/c-Met TKs. We synthesized the target compounds via a new single pot three-component reaction. The cytotoxic activity of synthesized compounds was conducted against HCT-116 colorectal cancer cell line. Compounds 3c and 3e exhibited the highest cytotoxic activity against HCT-116 cell line (IC(50) 1.184 and 3.403 µM, respectively). The in vitro enzyme inhibitory activity was carried out against both VEGFR-2 and c-Met TKs. Compound 3e has the highest inhibitory activity against both VEGFR-2/c-Met (IC(50) = 83 and 48 nM, respectively). Docking studies showed that α-oxo moiety in quinazoline ring formed hydrogen bond HB with Met1160 residue in the adenine region of c-Met TK.
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spelling pubmed-106161132023-11-01 Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation Hassan, Abdelfattah Mosallam, Ahmed M. Ibrahim, Amal O. A. Badr, Mohamed Abdelmonsef, Aboubakr H. Sci Rep Article Multitarget anticancer drugs are more superior than single target drugs regarding patient compliance, drug adverse effects, drug-drug interactions, drug resistance as well as pharmaceutical industry economics. Dysregulation of both VEGFR-2 and c-Met tyrosine kinases (TKs) could result in development and progression of different human cancers. Herein, we reported a novel series of 3-phenylquinazolin-2,4(1H,3H)-diones with thiourea moiety as dual VEGFR-2/c-Met TKs. Compared to sorafenib, cabozantinib went behind VEGFR-2 inhibition to target c-Met TK. The dual VEGFR-2/c-Met inhibitory activity of cabozantinib is due to a longer HB domain than that of sorafenib. Based on pharmacophore of cabozantinib analogues, we designed new dual VEGFR-2/c-Met TKs. We synthesized the target compounds via a new single pot three-component reaction. The cytotoxic activity of synthesized compounds was conducted against HCT-116 colorectal cancer cell line. Compounds 3c and 3e exhibited the highest cytotoxic activity against HCT-116 cell line (IC(50) 1.184 and 3.403 µM, respectively). The in vitro enzyme inhibitory activity was carried out against both VEGFR-2 and c-Met TKs. Compound 3e has the highest inhibitory activity against both VEGFR-2/c-Met (IC(50) = 83 and 48 nM, respectively). Docking studies showed that α-oxo moiety in quinazoline ring formed hydrogen bond HB with Met1160 residue in the adenine region of c-Met TK. Nature Publishing Group UK 2023-10-30 /pmc/articles/PMC10616113/ /pubmed/37903949 http://dx.doi.org/10.1038/s41598-023-45687-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hassan, Abdelfattah
Mosallam, Ahmed M.
Ibrahim, Amal O. A.
Badr, Mohamed
Abdelmonsef, Aboubakr H.
Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation
title Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation
title_full Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation
title_fullStr Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation
title_full_unstemmed Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation
title_short Novel 3-phenylquinazolin-2,4(1H,3H)-diones as dual VEGFR-2/c-Met-TK inhibitors: design, synthesis, and biological evaluation
title_sort novel 3-phenylquinazolin-2,4(1h,3h)-diones as dual vegfr-2/c-met-tk inhibitors: design, synthesis, and biological evaluation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616113/
https://www.ncbi.nlm.nih.gov/pubmed/37903949
http://dx.doi.org/10.1038/s41598-023-45687-y
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