Potent androgen antagonists based on carborane as a hydrophobic core structure.
Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable chemical and thermal stability and hydrophobic character. These features may allow application of carboranes as a new hydrophobic core structure in biologically active molecules that interact hydrophobically with receptors. We report here the design and synthesis of novel androgen antagonists bearing carborane. The most potent compounds, the arylcarborane derivatives 6e and 6i, exhibited antiandrogenic activity greater than that of the well-known antiandrogen hydroxyflutamide in reporter gene assay using NIH3T3 cells transfected with a human AR expression plasmid, as well as in cell growth inhibition assay using androgen-dependent SC-3 cells. Further development of the potent carborane-containing androgen antagonists described here, having a new skeletal structure and unique characteristics, may yield novel therapeutic agents, especially selective androgen receptor modulators.
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Japan.
Shinya
S
Fujii
Tokuhito
T
Goto
Kiminori
K
Ohta
Yuichi
Y
Hashimoto
Tomoharu
T
Suzuki
Shigeru
S
Ohta
Yasuyuki
Y
Endo
D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D001880:Boranes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011869:Radioligand Assay; D011944:Receptors, Androgen / Q000235:genetics; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
C502818:1-hydroxymethyl-12-(3-cyanophenyl)-1,12-dicarba-closo-dodecaborane; C502817:1-hydroxymethyl-12-(3-nitrophenyl)-1,12-dicarba-closo-dodecaborane; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D001880:Boranes; D001896:Boron Compounds; D011944:Receptors, Androgen