Boron clusters for medicinal drug design: Selective estrogen receptor
modulators bearing carborane*
Yasuyuki Endo1, Tomohiro Yoshimi1, and Chisato Miyaura2
1Tohoku Pharmaceutical University, Sendai
981-8558, Japan; 2Tokyo University of Pharmacy and Life Science,
Hachioji, Tokyo 192-0392, Japan
Abstract: The molecular shape and hydrophobicity of dicarba-closo
-dodecaboranes may allow a new medical application as biologically active
molecules. Recently, we have developed potent estrogen receptor (ER)
agonists bearing carborane cage. The most potent compound (BE120) exhibited
activity at least several times greater than that of 17 beta-estradiol
in luciferase reporter gene assay and ER alpha binding. We also designed
and synthesized estrogen antagonists on the basis of the structure of
BE120, and we noticed the characteristic features of compound (BE360)
having carborane cage and two phenols. The ER binding affinity of BE360
is comparable to that of estradiol. To examine in vivo estrogenic activity
of the compound in bone, ovariectomized (OVX) mice were given BE360
or estradiol subcutaneously for 4 weeks. Treatment with BE360 at 1�30
�g/day dose-dependently restored bone loss in OVX mice to sham level
without estrogenic action in uterus. These results suggest its possible
application to osteoporosis as a new type of selective ER modulator.
*Lecture presented at the XIth International Meeting
on Boron Chemistry (IMEBORON XI), Moscow, Russia, 28 July - 2 August
2002. Other presentations are published in this issue,
pp. 1157-1355.
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