Estrogenic affinity labels: synthesis, irreversible receptor binding, and bioactivity of aziridine-substituted hexestrol derivatives.
Estrogenic affinity labels: synthesis, irreversible receptor binding, and bioactivity of aziridine-substituted hexestrol derivatives.
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雌激素亲和标签：氮丙啶取代的己雌酚衍生物的合成、不可逆受体结合和生物活性。
DOI：
10.1021/jm00388a015
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发表时间：
1987
影响因子：
7.3
通讯作者：
Katzenellenbogen,BS
中科院分区：
文献类型：
--
作者：
Zablocki,JA;Katzenellenbogen,JA;Carlson,KE;Norman,MJ;Katzenellenbogen,BS
为了开发雌激素受体的亲和标记物，其将是雌激素激动剂，而不是拮抗剂，我们制备了几种在侧链上具有氮丙啶官能团的强效非甾体雌激素己烷雌酚（（3R*，4S*）-3，4-双（4-羟基苯基）己烷）的氮丙啶衍生物。三个官能团连接己雌酚配体和氮丙啶：羰基（酮或酯）、硫醚或亚甲基链。这些衍生物对雌激素受体的表观竞争结合亲和力为雌二醇的1.8%至25%，并且它们中的大多数与受体以时间依赖性的、不可逆的方式结合，尽管这种结合的速率和效率变化很大，通常在结构上具有相对较小的变化。这与需要受体结合位点中的活化和反应残基的精确对齐的不可逆附着一致。在MCF-7人乳腺癌细胞中研究了这些氮丙啶衍生物的雌激素和抗雌激素活性。大多数化合物是激动剂，其中一种是拮抗剂。衍生（6 R *，7S*）-1-N-氮丙啶基-6，7-双（4-羟基苯基）-5-壬酮（酮基-壬雌酚氮丙啶3）似乎具有最理想的行为。它是一种激动剂，它与受体不可逆地、有效地、快速地结合。亲和标记的概念，其中可逆结合配体被加工成能够共价标记结合蛋白的化学反应性衍生物，已经有效地应用于开发类固醇受体的共价标记剂。1光化学反应性和亲电性衍生物都已制备好，并对雌激素、雄激素、孕激素和皮质类固醇受体进行了标记研究。1通常，亲和标记剂具有高共价标记选择性，
To develop an affinity label for the estrogen receptor that would be an estrogen agonist, rather than antagonist, we prepared several aziridine derivatives of the potent nonsteroidal estrogen hexestrol ((3R*, 4S*)-3, 4-bis (4-hydroxyphenyl) hexane) bearing an aziridine function on the side chain. Three functional groups link the hexestrol ligand and the aziridine: a carbonyl group (ketone or ester), a thioether, or a methylene chain. The apparent competitive binding affinity of these derivatives for the estrogen receptor ranges from 1.8% to 25% that of estradiol, and most of them bind in a time-dependent, irreversible niannefwith the receptor, although the rate and efficiency of this binding vary widely, often with relatively small changes in structure. This is consistent with the irreversible attachment requiring a precise alignment of activating and reacting residues in the binding site of the receptor. The estrogenic and antiestrogenic activity of these aziridine derivatives wás investigated in MCF-7 human breast cancer cells. Most of the compounds are agonists, with one being an antagonist. The derivative (6R*, 7S*)-l-jV-aziridinyl-6, 7-bis (4-hydroxyphenyl)-5-nonanone (keto-nonéstrol aziridine 3) appearsto have the most ideal behavior Of the estrogenic affinity labeling agents prepared: It is an agonist, and it bindsto receptor irreversibly, efficiently, and quite rapidly.The affinity labeling concept, whereby reversibly binding ligands are elaborated into chemically reactive derivatives capable of covalently labeling binding proteins, has been applied effectively to develop covalent labeling agents for steroid receptors. 1 Both photochemicallyreactive and electrophilic derivatives have been prepared, and labeling studies have been conducted with estrogen, androgen, progestin, and corticosteroid receptors. 1 In general, the affinity labeling agents have high covalent labeling selec-