Synthesis and aromatase inhibitory activity of flavanones.
OBJECTIVE
Aromatase inhibitors are known to prevent the conversion of androgens to estrogens and play a significant role in the treatment of estrogen dependent diseases such as breast cancer. Some flavonoids have been reported as potent aromatase inhibitors; therefore, in an effort to develop novel anti breast cancer agents, B ring substituted flavanones with a 7-methoxy group on A ring were synthesized and tested to assess their ability to inhibit aromatase activity and to determine the optimal B ring substitution pattern.


METHODS
A series of flavanones was prepared by cyclisation of 2'-hydroxychalcones previously obtained by Claisen-Schmidt condensation and the aromatase inhibitory activity of these compounds was investigated using human placental microsomes and radiolabeled [1,2,6,7-(3)H]-androstenedione as substrate.


RESULTS
Almost all flavanones exhibited inhibitory effect on the aromatase activity but their potency was dependent on their B ring substitution pattern. Hydroxylation at position 3' and/or 4' enhanced the anti-aromatase activity; thus, 3',4'-dihydroxy-7-methoxyflavanone was found to be twice more potent than aminoglutethimide, the first aromatase inhibitor clinically used.


CONCLUSIONS
These results indicated that these flavanones could be considered as potential anti breast cancer agents through the inhibition of aromatase activity and allowed us to select some of these compounds as skeleton for the development of flavonoid structurally-related aromatase inhibitors.
Pouget
Christelle
C
UPRES EA 1085, Biomolécules et Cibles Cellulaires Tumorales-Prolifération cellulaire et inhibition enzymatique Faculté de Pharmacie, Limoges, France.
Fagnere
Catherine
C
Basly
Jean-Philippe
JP
Besson
Anne-Elise
AE
Champavier
Yves
Y
Habrioux
Gerard
G
Chulia
Albert-Jose
AJ
D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology
D047072:Aromatase Inhibitors; D005419:Flavonoids; D001141:Aromatase