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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/15/4757 |
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| author | Mai Khater Kimberly A. Watson Samuel Y. Boateng Francesca Greco Helen M. I. Osborn |
| author_facet | Mai Khater Kimberly A. Watson Samuel Y. Boateng Francesca Greco Helen M. I. Osborn |
| author_sort | Mai Khater |
| collection | DOAJ |
| 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 (<b>5a</b>,<b>b</b>) with reported anticancer activity, and derivatives (<b>4b</b> and <b>6a</b>), 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 (<b>4b</b>, <b>5a</b>,<b>b</b> and <b>6a</b>) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, <b>5a</b> and <b>5b</b> subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. <b>5b</b> displayed the best docking fit with VEGFR2 in an in silico study, followed by <b>5a</b>, 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. |
| first_indexed | 2024-03-09T10:06:28Z |
| format | Article |
| id | doaj.art-57e415d7fad841c7a44140bdbfeea439 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T10:06:28Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-57e415d7fad841c7a44140bdbfeea4392023-12-01T23:02:55ZengMDPI AGMolecules1420-30492022-07-012715475710.3390/molecules27154757Halogenated Flavonoid Derivatives Display Antiangiogenic ActivityMai Khater0Kimberly A. Watson1Samuel Y. Boateng2Francesca Greco3Helen M. I. Osborn4School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UKInstitute of Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Whiteknights, Berkshire RG6 6AS, UKInstitute of Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Whiteknights, Berkshire RG6 6AS, UKSchool of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UKSchool of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UKAntiangiogenic 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 (<b>5a</b>,<b>b</b>) with reported anticancer activity, and derivatives (<b>4b</b> and <b>6a</b>), 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 (<b>4b</b>, <b>5a</b>,<b>b</b> and <b>6a</b>) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, <b>5a</b> and <b>5b</b> subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. <b>5b</b> displayed the best docking fit with VEGFR2 in an in silico study, followed by <b>5a</b>, 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.https://www.mdpi.com/1420-3049/27/15/4757angiogenesisflavonoidsflavonescancerantiangiogenicSAR |
| spellingShingle | Mai Khater Kimberly A. Watson Samuel Y. Boateng Francesca Greco Helen M. I. Osborn Halogenated Flavonoid Derivatives Display Antiangiogenic Activity Molecules angiogenesis flavonoids flavones cancer antiangiogenic SAR |
| 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 | angiogenesis flavonoids flavones cancer antiangiogenic SAR |
| url | https://www.mdpi.com/1420-3049/27/15/4757 |
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