Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens
Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens
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DOI：
10.1021/tx000208y
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发表时间：
2001-03-01
影响因子：
4.1
通讯作者：
Sheehan, DM
中科院分区：
文献类型：
--
作者：
Fang, H;Tong, WD;Sheehan, DM
了解一种化学物质的结构要求，以显示雌激素受体（ER）的结合已经在各个领域的重要。这些知识已被直接或间接地应用于设计人类雌激素替代疗法的药物，并确定雌激素内分泌干扰物。本文报道了基于总共230种化学物质的结构-活性关系（SAR），包括天然和外源性雌激素。使用经验证的ER竞争性结合试验产生活性，其涵盖10（6）倍范围。本研究的重点是不同的ER配体之间的结构共性的鉴定。它提供了异种雌激素在结构上如何类似于内源性17 β-雌二醇（E-2）和合成雌激素己烯雌酚（DES）的总体情况。在SAR分析的基础上，使用E-2作为模板，发现五个区分标准对于异种雌激素活性是必不可少的：（1）模拟3-OH的酚环的H-键合能力，（2）模拟17 β-OH和3-和17 β-OH之间的O-O距离的H-键供体，（3）模拟空间7 α-和11 β-取代基的精确空间疏水中心，（4）疏水性，和（5）环结构。酚类的S-位H-键合能力是ER结合的重要要求。这有助于作为H-键供体和受体，尽管主要作为供体。然而，17 β-OH仅作为H-键供体贡献。空间疏水性主体基团的精确空间（大小和方向）与17 β-OH一样重要。在可以进行直接比较的情况下，强雌激素倾向于更疏水，刚性环结构有利于ER结合。从这项研究中获得的知识合理化为一组层次规则，这将是有用的指导识别潜在的雌激素。
Understanding structural requirements for a chemical to exhibit estrogen receptor (ER) binding has been important in various fields. This knowledge has been directly and indirectly applied to design drugs for human estrogen replacement therapy, and to identify estrogenic endocrine disrupters. This paper reports structure-activity relationships (SARs) based on a total of 230 chemicals, including both natural and xenoestrogens. Activities were generated using a validated ER competitive binding assay, which covers a 10(6)-fold range. This study is focused on identification of structural commonalities among diverse ER ligands. It provides an overall picture of how xenoestrogens structurally resemble endogenous 17 beta -estradiol (E-2) and the synthetic estrogen diethylstilbestrol (DES). On the basis of SAR analysis, five distinguishing criteria were found to be essential for xenoestrogen activity, using E-2 as a template: (1) H-bonding ability of the phenolic ring mimicking the 3-OH, (2) H-bond donor mimicking the 17 beta -OH and O-O distance between 3- and 17 beta -OH, (3) precise steric hydrophobic centers mimicking steric 7 alpha- and 11 beta -substituents, (4) hydrophobicity, and (5) a ring structure. The S-position H-bonding ability of phenols is a significant requirement for ER binding. This contributes as both a H-bond donor and acceptor, although predominantly as a donor. However, the 17 beta -OH contributes as a H-bond donor only. The precise space (the size and orientation) of steric hydrophobic bulk groups is as important as a 17 beta -OH. Where a direct comparison can be made, strong estrogens tend to be more hydrophobic, A rigid ring structure favors ER binding. The knowledge derived from this study is rationalized into a set of hierarchical rules that will be useful in guidance for identification of potential estrogens.