Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125, USA.
J Med Chem. 2010 Aug 26;53(16):6153-63. doi: 10.1021/jm100610w.
Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.
大豆黄酮（1）是一种天然的雌激素异黄酮。我们在这里报告，通过简单的 7-羟基氢的烷基取代，1 可以转化为抗雌激素配体。为了测试这种结构修饰对所得化合物激素活性的影响，设计并合成了一系列大豆黄酮类似物。当 MCF-7 细胞用类似物处理时，异丙基（3d）、异丁基（3f）、环戊基（3g）和吡喃基（2）取代氢得到的类似物抑制细胞增殖、雌激素诱导的转录活性和雌激素受体（ER）调节孕激素受体（PgR）基因表达。然而，羟基质子的甲基（3a）和乙基（3b）取代仅导致雌激素活性的适度降低。这些结果表明了大豆黄酮从 ER 激动剂向拮抗剂转化的结构要求。在异种移植小鼠模型中，发现最有效的类似物 2 可降低体内雌激素刺激的 MCF-7 细胞肿瘤发生。
