To increase the diversity of estrogen receptor (ER) ligands having novel structures and activities, series of selenophene derivatives with a basic side chain (BSC) were synthesized and their biological activity as subtype-selective antagonists for the ER was explored. Compared with the selenophenes without a BSC, most compounds showed an increase in binding affinity, and several compounds displayed enhanced antagonist potency and antiproliferative activity. Especially, compound 16c exhibited excellent transcriptional activity for ERα (IC₅₀ = 13 nM) which made this compound the most potent antagonist for ERα of the whole series and is 66-fold better than the best selenophene compound without a BSC. Moreover, several compounds showed values of IC₅₀ better than that of 4-hydroxytamoxifen in breast cancer MCF-7 cells. The modeling study indicated that the basic side chain might contribute to their increased antagonist potency and antiproliferative activity. These new ligands have the potential to be further developed as novel agents to improve therapeutics that target the estrogen receptor.

中文翻译：

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合理设计和优化具有基本侧链的硒代苯作为乳腺癌治疗的新型有效选择性雌激素受体调节剂（SERM）

为了增加具有新颖结构和活性的雌激素受体（ER）配体的多样性，合成了一系列具有基本侧链（BSC）的硒烯衍生物，并探讨了其作为ER亚型选择性拮抗剂的生物学活性。与没有BSC的硒代苯酚相比，大多数化合物显示出结合亲和力的增加，并且几种化合物显示出增强的拮抗剂效力和抗增殖活性。尤其是，化合物16c对ERα表现出优异的转录活性（IC ₅₀ = 13 nM），这使该化合物成为整个系列中最有效的ERα拮抗剂，比没有BSC的最佳硒基化合物好66倍。此外，几种化合物的IC ₅₀值在乳腺癌MCF-7细胞中优于4-羟基他莫昔芬。建模研究表明，基本侧链可能有助于增加其拮抗剂效力和抗增殖活性。这些新的配体有潜力被进一步开发为新型药物，以改善靶向雌激素受体的治疗药物。