Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents
Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents
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DOI：
10.1016/j.bmc.2017.07.067
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发表时间：
2017-10-15
影响因子：
3.5
通讯作者：
Shimohigashi, Yasuyuki
中科院分区：
文献类型：
--
作者：
Torikai, Kohei;Koga, Rintaro;Shimohigashi, Yasuyuki
雌激素发挥着无可争议的重要生理作用，但终生暴露于雌激素也与乳腺癌的发展有关。此外，不平衡的雌激素水平与各种症状如骨质疏松症和更年期疾病有关。为了改善这种雌激素失衡，具有调节特性的雌激素试剂显示出有希望的潜力。在此，我们报告了一个12-芳基苯并吖啶库的建设，通过多样性为导向的策略，提供无毒的雌激素和抗雌激素药物。在分子边缘具有羟基的衍生物表现出对雌激素受体α（ER α）和ER β的强结合亲和力（IC 50 <μ M），同时结合雌激素相关受体γ（ERR γ），即，没有观察到雌激素经常触发不利事件的孤儿核受体。这些发现提供了宝贵的见解12-芳基苯并吖啶作为一种新的平台，选择性雌激素受体调节剂（SERM）的发展。(C)2017爱思唯尔有限公司版权所有
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor alpha (ER alpha) and ER beta (IC50 < mu M), while binding to the estrogen-related receptor gamma (ERR gamma), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs). (C) 2017 Elsevier Ltd. All rights reserved.