Background: Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-
containing polyhedral boron-cluster compounds having remarkable thermal sta
bility and exceptional hydrophobicity. Applications of the unique structura
l and chemical properties offered by icosahedral carboranes in boron neutro
n capture therapy have received increasing attention over the past 30 years
. However, these features of carboranes may allow another application as a
hydrophobic pharmacophore in biologically active molecules that interact hy
drophobically with receptors.
Results: We have designed candidate estrogen-receptor-binding compounds hav
ing carborane as a hydrophobic skeletal structure and synthesized them. The
most potent compound bearing a carborane cage exhibited activity at least
10-fold greater than that of 17 beta -estradiol in the luciferase reporter
gene assay. Estrogen receptor-alpha -binding data for the compound were con
sistent with the results of the luciferase reporter gene assay. The compoun
d also showed potent in vivo effects on the recovery of uterine weight and
bone loss in ovariectomized mice.
Conclusion: Further development of the potent carborane-containing estrogen
ic agonists described here, having a new skeletal structure and unique char
acteristics, should yield novel therapeutic agents, especially selective es
trogen receptor modulators. Furthermore, the suitability of the spherical c
arborane cage for binding to the cavity of the estrogen receptor-alpha liga
nd-binding domain should provide a basis for a similar approach to developi
ng novel ligands for other steroid receptors. (C) 2001 Elsevier science Ltd
. All rights reserved.