使用金属催化偶联反应合成新型雌激素受体拮抗剂及其生物学活性的表征。

Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity.

机构信息

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, United States.

出版信息

J Med Chem. 2013 Apr 11;56(7):2779-90. doi: 10.1021/jm3013773. Epub 2013 Mar 26.

Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα and showed that they could tightly bind to the ERα in a manner similar to that of ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780.

雌激素受体（ER）拮抗剂在治疗 ER 阳性人乳腺癌方面具有重要价值。在这项研究中，我们设计并合成了九种新型 17β-雌二醇（E2）衍生物，其 C-7α 位连接了一个大侧链，并通过体外生物测定法测定了它们的 ER 拮抗活性。其中四种衍生物在荧光素酶报告基因测定中显示出对 ERα 转录激活活性的强烈抑制作用，并阻断了 ERα 与共激活剂的相互作用。同样，这些衍生物也强烈抑制了 ERα 阳性人乳腺癌细胞的生长。通过计算 docking 分析来模拟这些拮抗剂与人 ERα 的相互作用，表明它们可以以类似于纯 ER 拮抗剂 ICI-182,780 的方式与 ERα 紧密结合。这些结果提供了一个例子，即在 E2 的 C-7α 位连接一个大侧链可以产生具有与 ICI-182,780 相当的 ER 亲和力的 ER 拮抗剂。