Novel estrogen receptor (ER) modulators containing various hydrophobic bent-core structures.
We previously discovered m-carborane-containing estrogen receptor (ER) modulator 4, which exhibits weak ER-agonistic and antagonistic activities in transactivation assays. With the aim of developing novel ER partial agonists, we designed and synthesized various analogues of 4 with a bent-core structure, that is, pseudo cyclic structure (5), tetrahydropyrimidinone (6), m-benzene (7), adamantane (8), and 9,10-dimethyl-m-carborane (9), in place of the m-carborane moiety. Compound 9 showed greater binding affinity than 4 in ER-binding assay using [6,7-(3)H]-17β-estradiol and was a more effective partial agonist than 4 in MCF-7 cell proliferation assay. It appears to be a promising candidate as a selective ER modulator (SERM).
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Kiminori
K
Ohta
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Takumi
T
Ogawa
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Asako
A
Kaise
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: yendo@tohoku-pharm.ac.jp.
Yasuyuki
Y
Endo
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha
Bent-core structure; Carborane; Estrogen; Hydrophobic; SERM