Synthesis and Aromatase Inhibitory Activity of Flavanones
DISCUSSION
291
catechols abolished estrogenic effect (13). Therefore, besides
the potent aromatase inhibitory effect exhibited by 3Ј,4’-
dihydroxy-7-methoxyflavanone, this compound might be
without estrogenic activity and could actually be considered
as a potential anti-breast cancer agent.
Finally, on the basis of the studies reported herein, 3Ј-
hydroxy-7-methoxyflavanone 2b and 3Ј,4’-dihydroxy-7-
methoxyflavanone 6b have been selected for further modu-
lation on C ring in order to develop flavonoid structurally-
related aromatase inhibitors.
Different studies have demonstrated that several natu-
rally occurring flavonoids such as 7-hydroxyflavanone, 7-
hydroxyflavone, naringenin (5,7,4’-trihydroxyflavanone),
apigenin (5,7,4’-trihydroxyflavone), luteolin (5,7,3Ј,4’-tetra-
hydroxyflavone) or eriodictyol (5,7,3Ј,4’-tetrahydroxyflava-
none) were potent aromatase inhibitors (3-7,12). However,
most of these compounds were also found to display estro-
genic activity (9,13). Structure-activity relationships clearly
indicated that a 7-hydroxy group was the substituent essential
for enhanced aromatase inhibitory activity but flavonoids
with such a substituent were found to be invariably estro-
genic.
In contrast, 7-methoxyflavanone did not display estro-
genic activity (9,10) and exhibited an aromatase inhibitory
effect (7) as well as an antiproliferative activity on MCF-7
breast cancer cells (8). These data may suggest that pharma-
comodulation of the B ring of this flavanone could lead to
compounds having a balance between different anti breast
cancer activities.
The present results demonstrated that some of the
synthesized flavanones such as compounds 2b, 4b, 6b, or 9b
were potent aromatase inhibitors which indicated that hy-
droxylations on B ring may be required to obtain high aro-
matase inhibitory effect. Thus, the activity exhibited by 3Ј-
hydroxy-7-methoxyflavanone 2b and 3Ј,4’-dihydroxy-7-
methoxyflavanone 6b relative to 7-methoxyflavanone and 4’-
hydroxy-7-methoxyflavanone 4b respectively, clearly showed
that the presence of an additional 3Ј-hydroxy group enhanced
the anti-aromatase activity. These findings are consistent with
the increased potency we observed with eriodictyol (5,7,3Ј,4’-
tetrahydroxyflavanone) relative to naringenin (5,7,4’-trihy-
droxyflavanone) (12). Among all the flavanones tested, 3Ј,4’-
dihydroxy-7-methoxyflavanone 6b was found to be the most
active and twice more potent than aminoglutethimide, the
first aromatase inhibitor clinically used. Therefore, structure-
activity relationships with flavanones seem to indicate that
two hydroxy groups at position 3Ј and 4’ are the optimal
pattern of B ring substitution that gives rise to anti-aromatase
activity.
ACKNOWLEDGMENTS
The authors are grateful to the Region Limousin for its
financial support and for the grant awarded to C. Pouget.
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We also demonstrated that the presence of halogen at-
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nones did not influence aromatase inhibitory effect whereas
the results for the aromatase inhibition by azole-type inhibi-
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(14).
Further experiments are currently undergoing to exam-
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MCF-7 breast cancer cells growth and to interact with estro-
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were invariably estrogenic whereas hydroxylations that create