Aliphatic substitution of o-carboranyl phenols enhances estrogen receptor beta selectivity.
The two subtypes of estrogen receptor (ER), ERα and ERβ, differ greatly in expression pattern and biological functions, and ERβ-selective ligands candidates to treat immune-related disorders. ERβ-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand's interaction with Met421 to selectively decrease the affinity for ERα (the equivalent residue in ERβ is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ERβ-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ERβ selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ERβ selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University.
Kiminori
K
Ohta
Takumi
T
Ogawa
Asako
A
Kaise
Akifumi
A
Oda
Yasuyuki
Y
Endo
D001667:Binding, Competitive; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells / Q000187:drug effects; D008715:Methionine; D062105:Molecular Docking Simulation; D019800:Phenol / Q000737:chemistry*; D013329:Structure-Activity Relationship
C000597991:1-(4-hydroxyphenyl)-2-n-propyl-1,2-dicarba-closo-dodecaborane; D001896:Boron Compounds; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D019800:Phenol; D008715:Methionine