Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist
Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist
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鉴定 10-脱氢甘脲菌素 E 作为选择性人雌激素受体 α 部分激动剂
DOI：
10.1016/j.bioorg.2019.102977
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发表时间：
2019
影响因子：
5.1
通讯作者：
Nemoto Kiyomitsu
中科院分区：
文献类型：
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作者：
Saito Nao;Kawase Keiko;Yamashita Naoya;Tang Yingzhan;Wang Ying;Wang Jian;Liu Yongxiang;Li Ning;Li Wei;Cheng Mao-Sheng;Koike Kazuo;Kanno Yuichiro;Nemoto Kiyomitsu
选择性雌激素受体调节剂（selective estrogen receptor modulators，SERM）是雌激素受体（estrogen receptor，ER）的激动剂或拮抗剂，在乳腺癌、绝经后综合征、骨质疏松症、心血管疾病等疾病中有着广泛的应用。然而，目前的SERM也可能增加严重副作用的风险并引发耐药性。在此，一个筛选程序，旨在寻找新的SERM，导致一系列的2-芳基苯并呋喃的化合物的鉴定，是ERα的配体，当应用高斯荧光素酶报告基因分析。化学合成了10-脱氢氧化甘氨酰乌拉林E（T9），T9对ERα阳性乳腺癌细胞具有抗雌激素活性和抗增殖活性。T9预处理可抑制雌激素反应基因GREB 1的mRNA表达。此外，通过计算机模拟对接研究，我们证明了T9与ERα直接相互作用。这些结果表明，T9是SERM的候选化合物，也是SERM选择活性基础的种子化合物。
Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying theGaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized.T9showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment ofT9prevented the mRNA expression ofGREB1, which is an estrogen response gene. Furthermore, by anin silicodocking simulation study we demonstrated thatT9showed interactions directly to ERα. Taken together, these results demonstrated thatT9is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs.