Aromatase inhibition by bioavailable methylated flavones

Abstract

Previous studies have shown chrysin, 7-hydroxyflavone and 7,4′-dihydroxyflavone to be the most potent flavonoid inhibitors of aromatase. However, very poor oral bioavailability is a major limitation for the successful use of dietary flavonoids as chemopreventive agents. We have recently shown that methylated flavones, including 5,7-dimethoxyflavone, 7-methoxyflavone and 7,4′-dimethoxyflavone, are much more resistant to metabolism than their unmethylated analogs and have much higher intestinal absorption. In this study, we examined these fully methylated flavones as potential aromatase inhibitors for the prevention and/or treatment of hormone-dependent cancers. Whereas 5,7-dimethoxyflavone had poor effect compared to its unmethylated analog chrysin, 7-methoxyflavone and 7,4′-dimethoxyflavone were almost equipotent to their unmethylated analogs with IC 50 values of 2 to 9 μM. Thus, some fully methylated flavones appear to have great potential as cancer chemopreventive/chemotherapeutic agents.

Synthetic isoflavones and doping: A novel class of aromatase inhibitors?

“…Working solutions of testosterone (0.1, 0.2, 0.5, 1, 5, 10, 20 μM) were prepared from a 50 μM stock solution in methanol. Working solutions of inhibitors, prohibited drugs, and natural flavonoids, were prepared at different concentration, according to their IC25 , IC 50 , and IC 75 (formestane, anastrozole, and aminoglutethimide 0.4, 0.8, 1.2 μM; daidzein 1, 5, 10 μM; chrysin 0.35, 0.7, 1 μM; quercetin 25, 50, General structure of A, flavonoids and B, isoflavones and of C, methoxyisoflvone and D, ipriflavone 100 μM), in methanol. 29-31 Stock solution of methoxyisoflavone and ipriflavone (5, 10, 50 μM) were prepared in methanol.…”

Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition

“…In addition to these activities, chrysin has been reported to be an inhibitor of aromatase, an enzyme-converting testosterone into estrogen [21,33]. However, renoprotective effects of chrysin on diabetes-associated kidney dysfunction need to be defined [34].…”

“…Chrysin has been well documented for involving in various biological activities, including inflammation, cancer, and oxidative stress [18][19][20]. Chrysin has been reported to be an inhibitor of aromatase, an enzyme-converting testosterone into estrogen [21]. However, whether chrysin ameliorated renal structure and function by regulating diabetes-associated EMT in DN remained elusive.…”

Structurally Modified ‘Dietary Flavonoids’: Are these Viable Drug Candidates for Chemoprevention?

“…The probable reasons associated with the lack of bioavailability of these dietary flavonoids is akin to the common problems of druggability encountered often times in drug discovery/development scenario for many programs. The reported issues for the lack of bioavailability for flavonoids were ranging from lack of stability, excessive metabolism, permeability problems, lack of site specificity in distribution, rapid elimination etc [9][10][11][12][13].…”