Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

Estrogen
receptor α (ERα) is an important target for
the design of drugs such as tamoxifen (2a) and fulvestrant
(5). Three series of ER-ligands based on the benzoxepin
scaffold structure were synthesized: series I containing an acrylic
acid, series II with an acrylamide, and series III with a saturated
carboxylic acid substituent. These compounds were shown to be high
affinity ligands for the ER with nanomolar IC50 binding
values. Series I acrylic acid ligands were generally ERα selective.
In particular, compound 13e featuring a phenylpenta-2,4-dienoic
acid substituent was shown to be antiproliferative and downregulated
ERα and ERβ expression in MCF-7 breast cancer cells. Interestingly,
from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated
ERβ. A docking study of the benzoxepin ligands was undertaken.
Compound 13e is a promising lead for development as a
clinically relevant SERD, while compound 22 will be a
useful experimental probe for helping to elucidate the role of ERβ
in cancer cells.

雌激素受体α（Estrogen receptor α, ERα）是他莫昔芬（tamoxifen, 2a）、氟维司群（fulvestrant, 5）等药物研发的重要靶点。本研究基于苯并氧杂䓬（benzoxepin）骨架结构，合成了三类ER配体：I类带有丙烯酸取代基，II类带有丙烯酰胺取代基，III类带有饱和羧酸取代基。经检测，上述化合物均为高亲和力ER配体，其结合活性的半最大抑制浓度（IC50）达到纳摩尔级水平。I类丙烯酸取代型配体普遍表现出ERα选择性。尤为突出的是，带有苯基戊-2,4-二烯酸取代基的化合物13e可抑制MCF-7乳腺癌细胞增殖，并下调ERα与ERβ的表达水平。有趣的是，来自III类的苯氧基丁酸衍生物化合物22虽无抗增殖活性，却可选择性下调ERβ的表达。本研究还针对苯并氧杂䓬类配体开展了分子对接研究。化合物13e是极具开发潜力的先导化合物，有望开发为临床相关的选择性雌激素受体降解剂（Selective Estrogen Receptor Degraders, SERD）；而化合物22则可作为实用的实验探针，助力阐明ERβ在癌细胞中的作用机制。