Exploring quercetin and luteolin derivatives as antiangiogenic agents

Abstract

The formation of new blood vessels from the pre-existing vasculature (angiogenesis) is a crucial stage in cancer progression and, indeed, angiogenesis inhibitors are now used as anticancer agents, clinically. Here we have explored the potential of flavonoid derivatives as antiangiogenic agents. Specifically, we have synthesised methoxy and 4-thio derivatives of the natural flavones quercetin and luteolin, two of which (4-thio quercetin and 4-thio luteolin) had never been previously reported. Seven of these compounds showed significant (p < 0.05) antiangiogenic activity in an in vitro scratch assay. Their activity ranged from an 86% inhibition of the vascular endothelium growth factor (VEGF)-stimulated migration (observed for methoxyquercetin at 10 μM and for luteolin at 1 μM) to a 36% inhibition (for thiomethoxy quercetin at 10 μM). Western blotting studies showed that most (4 out of 7) compounds inhibited phosphorylation of the VEGF receptor-2 (VEGFR2), suggesting that the antiangiogenic activity was due to an interference with the VEGF/VEGFR2 pathway. Molecular modelling studies looking at the affinity of our compounds towards VEGFR and/or VEGF confirmed this hypothesis, and indeed the compound with the highest antiangiogenic activity (methoxyquercetin) showed the highest affinity towards VEGFR and VEGF. As reports from others have suggested that structurally similar compounds can elicit biological responses via a non-specific, promiscuous membrane perturbation, potential interactions of the active compounds with a model lipid bilayer were assessed via DSC. Luteolin and its derivatives did not perturb the model membrane even at concentrations 10 times higher than the biologically active concentration and only subtle interactions were observed for quercetin and its derivatives. Finally, cytotoxicity assessment of these flavonoid derivatives against MCF-7 breast cancer cells demonstrated also a direct anticancer activity albeit at generally higher concentrations than those required for an antiangiogenic effect (10 fold higher for the methoxy analogues). Taken together these results show promise for flavonoid derivatives as antiangiogenic agents.

Structural Insight into the In Vitro Anti-Intravasative Properties of Flavonoids

“…This concentration had no effects on the tube formation of vascular endothelial cells, another cell migratory process [63]. In fact, the migration of blood endothelial cells during angiogenesis depends on VEGF/VEGFR2 instead of MMP2/9, and quercetin interferes with VEGFR2 expression [64,65]. However, in lymph endothelial cells, the VEGF/VEGFR2 signaling is not observed during intravasation of MCF-7 cells [13].…”

Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives

“…In previous studies, some thioxoflavonones showed no or less antiproliferative activity in nine human cancer cell lines (A375, HCT‐15, BxPC3, MCF‐7, MCF‐7‐ADR, A431, A431/Pt, OV2008, and C13*) than correspondent flavones . However, we could find that a translation of carbonyl (CO) group into thiocarbonyl (CS) group could significantly improve their antiproliferative activities of the parent flavones on three human cancer cell lines (HeLa, HCC1954, and SK‐OV‐3).…”

“…Interestingly, the key role of sulfur‐containing small molecules and enzymes in a wide range of essential biological functions led researchers to focus intensely on developing new thio‐compounds to treat or prevent diseases, thioxoflavones have been reported to show special anticancer, antimicrobial, and neuroprotective activities .…”

Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

“…The pentahydroxy avone (quercetin) derivatives (5c-f) were obtained starting from pentahydroxy avone (purchased) according to Scheme 3 27,28 in 36% overall yield and with 99% purity by HPLC. This represents an improvement on the recently reported synthesis of 5f, both in terms of overall yield and purity 29 (22% overall yield and 95% purity).…”