Halogenated Flavonoid Derivatives Display Antiangiogenic Activity

Abstract

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.

Anticancer evaluation of new organometallic ruthenium(ii) flavone complexes

“…The biocompatibility of flavones ( 1 and 2 ) 30 alongside their ruthenium( ii ) metal complexes ( 1Ru and 2Ru ) with HUVEC cells was established using the trypan blue exclusion assay. A concentration four times higher ( i.e.…”

“…Thus combination of the S atom with the Ru(II)-arene presumably leads to better interaction with target proteins via several ways such as increasing the lipophilicity of the ligand. 30,39 The observed trends in antimigratory activities on both breast cancer cell lines were not concentration dependant. As shown in Fig.…”

“…Previous studies have reported a negative dose-response relationship of flavonoids or their metabolites on their cell adhesion and antiangiogenic effects. 30,40 However, further investigations are still needed to unfathom the algorithms of this dosageactivity interplay.…”

“…Synthesis of the parent flavonoids ( 1) and ( 2) followed the previously published protocol. 30,33 4.5.1. Synthesis of chlorido [(5-oxo-κO)-7-hydroxy-2-(4′chlorophenyl)-4H-chromen-4-onato-κO] (η 6 -p-cymene) ruthenium(II) (1Ru).…”

“…Compound 2 is a 4-thioflavone that showed significant in vitro antiproliferative, antiangiogenic and VEGFR2 phosphorylation inhibition activities in our previous studies. 23,[28][29][30] Furthermore, the 4-oxoflavone (1) was included in the study to gain additional insight on the contribution of the functional group at position number 4 not only on the free flavonoid's activity but also on the biological effects of complexation. Initially, a tube formation assay was utilised for the synthetic derivatives (1 and 2) alongside the novel complexes (1Ru and 2Ru) to establish their antiangiogenic potential on endothelial cells which are major contributors to the spread and growth of tumours.…”