ER subtype selectivity of m-carborane-containing phenols: C-alkyl groups on the m-carborane cage enhance ERα selectivity.
Estrogen receptor (ER) exhibits two subtypes, ERα and ERβ, whose biological functions are quite different despite expression in the same tissues. We developed diiodo-m-carborane derivative 3a, which showed 14-fold selectivity for ERβ with high binding affinity toward ERβ. Interestingly, introduction of an alkyl group into the carbon atom of the m-carborane cage of 3a markedly enhanced the binding affinity toward ERα and decreased affinity toward ERβ. C-n-propyl derivative 3d showed 28-fold selectivity for ERα in an ER binding assay and promoted proliferation of MCF-7 breast cancer cells. Docking simulation studies suggest that the directions of the n-propyl group and the diiodo substituent introduced on the m-carborane cage play important roles for the control of ER subtype selectivity. As 3a and 3d showed ERβ and ERα selectivity with high binding affinity, respectively, these ligands may be useful as biological tools to aid in understanding the different roles of ER subtypes.
['Ohta|Kiminori|K|', 'Ogawa|Takumi|T|', 'Kato|Koichi|K|', 'Oda|Akifumi|A|', 'Endo|Yasuyuki|Y|']
D000970:Antineoplastic Agents D001665:Binding Sites D001880:Boranes D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D047628:Estrogen Receptor alpha D047629:Estrogen Receptor beta D006801:Humans D008024:Ligands D061986:MCF-7 Cells D062105:Molecular Docking Simulation D015394:Molecular Structure D010636:Phenols D013329:Structure-Activity Relationship
Subtype selectivity Erα Estrogen receptor Carborane