Estrogenic activity of bis(4-hydroxyphenyl)methanes with cyclic hydrophobic structure
Estrogenic activity of bis(4-hydroxyphenyl)methanes with cyclic hydrophobic structure
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具有环状疏水结构的双(4-羟基苯基)甲烷的雌激素活性
DOI：
10.1016/j.bmc.2015.09.046
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发表时间：
2015
影响因子：
3.5
通讯作者：
Yasuyuki Endo
中科院分区：
文献类型：
--
作者：
Tomohiro Kojima;Takumi Ogawa;Souichiro Kitao;Manabu Sato;Akifumi Oda;Kiminori Ohta;Yasuyuki Endo
单烷基化双（4-羟基苯基）甲烷（例如，1)据报道对雌激素受体（ER）显示弱的结合亲和力。我们假设，在这些化合物中引入适当位置的疏水取代基将增加结合亲和力。事实上，我们发现带有3，3-二甲基环己基的双（4-羟基苯基）甲烷（7）显示出与雌二醇相当的有效ERα结合亲和力。可以在3，3-位引入更大的取代基而不降低亲和力。然而，取代基的位置是关键的：4，4-二甲基环己基衍生物（2）显示出非常弱的结合亲和力。在人乳腺癌细胞系MCF-7的细胞增殖试验中，具有高ER结合亲和力的化合物显示出主要的激动活性，以及在高浓度下的弱拮抗活性。对这些化合物及其衍生物的进一步结构-功能研究可能会导致更有选择性和更有效的雌激素受体调节剂的发展。
Monoalkylated bis(4-hydroxyphenyl)methanes (e.g.,1) are reported to show weak binding affinity for estrogen receptor (ER). We hypothesized that introduction of appropriately located hydrophobic substituents in these compounds would increase the binding affinity. Indeed, we found that bis(4-hydroxyphenyl)methane bearing a 3,3-dimethylcyclohexyl group (7) shows potent ERα binding affinity, comparable to that of estradiol. Bulkier substituents could be introduced at the 3,3-position without decreasing the affinity. However, the position of the substituents was critical: the 4,4-dimethylcyclohexyl derivative (2) showed very weak binding affinity. The compounds with high ER-binding affinity showed predominantly agonistic activity, together with weak antagonistic activity at high concentration, in cell proliferation assay with human breast cancer cell line MCF-7. Further structure–function studies of these compounds and their derivatives might lead to the development of more selective and potent estrogen receptor modulators.