The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium‐containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure–activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ‐selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2‐fluoro‐4‐hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2‐methyl‐4‐hydroxyphenyl)selenophene (2 b), bis(4‐fluoro‐3‐hydroxyphenyl)3‐bromoselenophene (6 f), and 2,3,5‐tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4‐hydroxytamoxifen in breast cancer MCF‐7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.

中文翻译：

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硒烯：将新元素引入非甾体雌激素受体配体的核心

具有外围酚和烷基取代基作为雌激素受体（ER）配体的主要结构基序的杂环核心元素的重要性已得到公认。在这项研究中，我们通过制备含硒杂环并探索这些硒烯对两种ERs，ERα和ERβ的活性，扩展了核心元素的结构多样性。对它们的ER结合亲和力进行仔细的结构-活性关系（SAR）分析表明，大多数硒烯是ERβ选择性的，苯酚取代基在硒烯核上的位置以及这些取代基的性质对其结合亲和力有显着影响。化合物双（2-氟-4-羟基苯基）硒烯（2 f）对ERβ具有最高的24.3的相对结合亲和力（RBA）。在转录测定中，发现大多数硒烯对两种ER亚型均表现出部分或全部激动剂活性，其中化合物bis（2-甲基-4-羟基苯基）硒烯（2 b），双（4-氟-3-羟基苯基）3-溴化硒烯（6 f）和2,3,5-三（羟苯基）噻吩（8 b和8 d）用作ERα的超激动剂; 然而，几种化合物表现出一系列的ERα或ERβ拮抗活性。少数硒代酚具有抗增殖活性，化合物8 c在乳腺癌MCF-7细胞中显示出与4-羟基他莫昔芬相似的抗增殖作用，但对正常的VERO细胞无毒。这些新的配体可作为开发新型药物的模型，从而导致靶向雌激素受体的改良疗法。