Synthesis and biological evaluation of (+/-)-abyssinone II and its analogues as aromatase inhibitors for chemoprevention of breast cancer.
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).
Maiti
Arup
A
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Cuendet
Muriel
M
Croy
Vicki L
VL
Endringer
Denise C
DC
Pezzuto
John M
JM
Cushman
Mark
M
D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001141:Aromatase / Q000737:chemistry; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D001943:Breast Neoplasms / Q000517:prevention & control*; D005260:Female; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D016588:Anticarcinogenic Agents; D047072:Aromatase Inhibitors; D005419:Flavonoids; C511702:abyssinone II; D001141:Aromatase