title: Synthesis and biological evaluation of novel m-carborane-containing estrogen receptor partial agonists as SERM candidates.
abstract: We designed and synthesized novel m-carborane-containing selective estrogen receptor modulator (SERM) candidates using previously reported m-carborane-containing ER partial agonist 1 as the lead compound. Biological activities were evaluated by means of ERα competitive binding assay and MCF-7 cell proliferation assay. Re-positioning the N,N-dimethylaminoethyloxy group at the para position of 1 to the meta position enhanced the ERα-binding affinity, and 4c showed the highest relative binding affinity (RBA: 83 vs 17β-estradiol = 100) among the tested compounds. Compound 4b showed the most potent ER-agonist activity (EC50: 1.4 nM) and the lowest maximal efficacy (Emax: 50%) in MCF-7 cell proliferation assay. Inhibition of 0.1 nM 17β-estradiol-induced MCF-7 cell proliferation by 4b (IC50: 0.4 μM) was at least 10 times more potent than that of the lead compound 1.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Kaise
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: yendo@tohoku-pharm.ac.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001896:Boron Compounds; D047628:Estrogen Receptor alpha; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators
keywords: Carborane; Estrogen receptor; Partial agonist; SERM