Potent estrogen agonists based on carborane as a hydrophobic skeletal structure - A new medicinal application of boron clusters

Citation
Y. Endo et al., Potent estrogen agonists based on carborane as a hydrophobic skeletal structure - A new medicinal application of boron clusters, CHEM BIOL, 8(4), 2001, pp. 341-355
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
CHEMISTRY & BIOLOGY
ISSN journal
1074-5521 → ACNP
Volume
8
Issue
4
Year of publication
2001
Pages
341 - 355
Database
ISI
SICI code
1074-5521(200104)8:4<341:PEABOC>2.0.ZU;2-R
Abstract
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.