Synthesis and Biological Evaluation of (±)-Abyssinone II and Its Analogues as Aromatase Inhibitors for Chemoprevention of Breast Cancer

Abstract

An efficient and economical synthesis of the naturally occurring aromatase inhibitor abyssinone II was performed. The synthesis features an optimized aromatic prenylation reaction in which an arylcopper intermediate is reacted with prenyl bromide to afford a key intermediate that was converted to a prenylated aromatic aldehyde. Condensation of the aldehyde with an o-hydroxyacetophenone under Claisen-Schmidt conditions afforded a chalcone that was deprotected and cyclized in the presence of sodium acetate in refluxing ethanol to afford (+/-)-abyssinone II. The synthesis proved to be versatile enough to provide an array of abyssinone II derivatives that were evaluated as aromatase inhibitors. Methylation of the 4'-hydroxyl group of (+/-)-abyssinone II resulted in a significant increase in aromatase inhibitory activity, and further smaller increases in activity resulted from the methylation of the 7-hydroxyl group and removal of the prenyl side chain. As a result of these structural changes, the most active flavanone of the series was 20 times more potent than (+/-)-abyssinone II (IC50 40.95 microM).

Intestinal Absorption Mechanisms of Prenylated Flavonoids Present in the Heat-Processed Epimedium koreanum Nakai (Yin Yanghuo)

“…6) showed that both absorptive permeability and the secretory permeability increased and the efflux ratio remained about the same in the presence of MRP inhibitor LTC 4 and BCRP inhibitor dipyridamole. However, in the presence of 20μM verapamil, the absorptive permeability significantly increased, whereas secretory permeability significantly decreased, which resulted in a 70% reduction in the efflux ratio (from 4.88 to 1.49).…”

“…1) are widely distributed in the plant world and have a variety of biological effects including anticancer and anti-aging (e.g., alleviating aging-related degenerative diseases) (1)(2)(3). Prenylated flavonoids also serve as lead compounds to the development of novel estrogen receptor agonists and antagonists (4). Several prenylated flavonoids (e.g., 8-prenylated-naringenin) are also widely consumed because they are present in hops that are used to make beer (5,6).…”

Dietary chalcones with chemopreventive and chemotherapeutic potential

“…Surprisingly, only one compound showed inhibition potential and it was less potent than racemic abyssinone II. The successful derivative featured two hydroxyl groups on the A ring and one methoxy group accompanied by a 3-methylbutyl-2-enyl substituent on B ring [112].…”

Egonol gentiobioside and egonol gentiotrioside from Styrax perkinsiae promote the biosynthesis of estrogen by aromatase

“…An in vitro recombinant expressed aromatase activity assay was conducted as described previously with minor modifications (Stresser et al, 2000;Maiti et al, 2007). In brief, the test compounds (5 ml) were preincubated with an NADPH regenerating system (45 ml of 2.6 mM NADP þ , 7.6 mM glucose-6-phosphate, 0.8 U/ml glucose-6-phosphate dehydrogenase, and 1 mg/ml albumin, in 50 mM potassium phosphate, pH 7.4) for 10 min at 37 1C before 50 ml of the enzyme and substrate mixture (40 pM recombinant aromatase and 0.4 mM dibenzylfluorescein in 50 mM potassium phosphate, pH 7.4) were added.…”