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Halogenated Flavonoid Derivatives Display Antiangiogenic Activity

Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones...

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Autores principales: Khater, Mai, Watson, Kimberly A., Boateng, Samuel Y., Greco, Francesca, Osborn, Helen M. I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331694/
https://www.ncbi.nlm.nih.gov/pubmed/35897938
http://dx.doi.org/10.3390/molecules27154757
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author Khater, Mai
Watson, Kimberly A.
Boateng, Samuel Y.
Greco, Francesca
Osborn, Helen M. I.
author_facet Khater, Mai
Watson, Kimberly A.
Boateng, Samuel Y.
Greco, Francesca
Osborn, Helen M. I.
author_sort Khater, Mai
collection PubMed
description Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40–55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4−C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target’s binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.
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spelling pubmed-93316942022-07-29 Halogenated Flavonoid Derivatives Display Antiangiogenic Activity Khater, Mai Watson, Kimberly A. Boateng, Samuel Y. Greco, Francesca Osborn, Helen M. I. Molecules Article Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40–55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4−C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target’s binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds. MDPI 2022-07-25 /pmc/articles/PMC9331694/ /pubmed/35897938 http://dx.doi.org/10.3390/molecules27154757 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
Khater, Mai
Watson, Kimberly A.
Boateng, Samuel Y.
Greco, Francesca
Osborn, Helen M. I.
Halogenated Flavonoid Derivatives Display Antiangiogenic Activity
title Halogenated Flavonoid Derivatives Display Antiangiogenic Activity
title_full Halogenated Flavonoid Derivatives Display Antiangiogenic Activity
title_fullStr Halogenated Flavonoid Derivatives Display Antiangiogenic Activity
title_full_unstemmed Halogenated Flavonoid Derivatives Display Antiangiogenic Activity
title_short Halogenated Flavonoid Derivatives Display Antiangiogenic Activity
title_sort halogenated flavonoid derivatives display antiangiogenic activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331694/
https://www.ncbi.nlm.nih.gov/pubmed/35897938
http://dx.doi.org/10.3390/molecules27154757
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