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

• Published in: Journal of medicinal chemistry Vol. 50; no. 12; pp. 2799 - 2806
• Main Authors: Maiti, Arup, Cuendet, Muriel, Croy, Vicki L, Endringer, Denise C, Pezzuto, John M, Cushman, Mark
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 14-06-2007
• Subjects: Anticarcinogenic Agents - chemical synthesis; Anticarcinogenic Agents - chemistry; Aromatase - chemistry; Aromatase Inhibitors - chemical synthesis; Aromatase Inhibitors - chemistry; Biological and medical sciences; Breast Neoplasms - prevention & control; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Female; Flavonoids - chemical synthesis; Flavonoids - chemistry; Humans; Medical sciences; Stereoisomerism; Structure-Activity Relationship; Tumors; Enzyme; Enzyme inhibitor; Breast cancer; Estrogen synthase; Malignant tumor; Anticarcinogen; Flavonoid; In vitro; Flavanone derivatives; Mammary gland diseases; Structure activity relation; Mammary gland; Chemical synthesis; Cancer
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070109i

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 μM).