Potent estrogen agonists based on carborane as a hydrophobic skeletal structure. A new medicinal application of boron clusters.
BACKGROUND
Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable thermal stability and exceptional hydrophobicity. Applications of the unique structural and chemical properties offered by icosahedral carboranes in boron neutron 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 hydrophobically with receptors.


RESULTS
We have designed candidate estrogen-receptor-binding compounds having 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 17beta-estradiol in the luciferase reporter gene assay. Estrogen receptor-alpha-binding data for the compound were consistent with the results of the luciferase reporter gene assay. The compound also showed potent in vivo effects on the recovery of uterine weight and bone loss in ovariectomized mice.


CONCLUSIONS
Further development of the potent carborane-containing estrogenic agonists described here, having a new skeletal structure and unique characteristics, should yield novel therapeutic agents, especially selective estrogen receptor modulators. Furthermore, the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-alpha ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.
Endo
Y
Y
Graduate School of Phamaceutical Sciences, University of Tokyo, Japan. yendo@mol.f.u-tokyo.ac.jp
Iijima
T
T
Yamakoshi
Y
Y
Fukasawa
H
H
Miyaura
C
C
Inada
M
M
Kubo
A
A
Itai
A
A
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D019556:COS Cells; D015195:Drug Design; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D017930:Genes, Reporter / Q000235:genetics; D006860:Hydrogen Bonding; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009929:Organ Size / Q000187:drug effects; D010024:Osteoporosis / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014591:Uterine Diseases / Q000188:drug therapy / Q000473:pathology; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D001896:Boron Compounds; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen; D004958:Estradiol