ESTROGEN RECEPTOR BINDING TOLERANCE OF 16-ALPHA-SUBSTITUTED ESTRADIOL DERIVATIVES
ESTROGEN RECEPTOR BINDING TOLERANCE OF 16-ALPHA-SUBSTITUTED ESTRADIOL DERIVATIVES
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DOI：
10.1016/0039-128x(88)90046-3
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发表时间：
1988-01-01
期刊：
影响因子：
2.7
通讯作者：
KATZENELLENBOGEN J A
中科院分区：
文献类型：
--
作者：
FEVIG T L;MAO M K;KATZENELLENBOGEN J A
为了检查雌激素受体对16 α-雌二醇的耐受性，在雌二醇中的取代基，我们已经合成了各种16 α-取代的雌激素，并通过竞争性放射性结合测定法测定它们对受体的结合亲和力。取代基的范围从小的单原子取代基（卤素）、双原子取代基（卤代甲基）到较大的烷基和最终具有各种官能团的烷基，包括荧光（硝基苯并恶二唑，NBD）和光反应性（硝基叠氮基苯基，NAP）基团。雌激素受体似乎对大的取代基有适度的耐受性：所有的卤素和卤代甲基取代基结合的亲和力至少是雌二醇的50%;在三原子烷基系列中，亲和力从炔丙基（44%）和烯丙基（38%）到丙基（5%）显著下降，这表明详细的空间限制或偏好不饱和。更大、更高度官能化的衍生物的亲和力范围为0.1 - 7%，其中最高亲和力的结合剂是苄基（5%）和4-苯氧基-2（E）-丁烯基（7%）;大多数最低亲和力的结合剂是大体积的荧光和光反应性衍生物。因此，雌激素受体对在16 α-位取代的雌二醇衍生物具有良好的耐受性。在具有中等体积的非极性基团的情况下，亲合性在位置上;然而，在具有较大体积的基团的情况下，亲合性低得多，并且高度依赖于取代基的极性和详细结构。
In order to examine the tolerance of the estrogen receptor for 16.alpha.-substituents in estradiol, we have synthesized various 16.alpha.-substituted estrogens and determined their binding affinity for receptor by a competitive radiometric binding assay. The substituents ranged from small, single-atom substituents (halogens), two-atom substituents (halomethyl groups), to larger alkyl groups and ultimately alkyl groups bearing various functionality, including fluorescent (nitrobenzoxadiazle, NBD) and photoreactive (nitroazidophenyl, NAP) groups. The estrogen receptor seems to have a moderate tolerance for bulky substituents: all of the halogen and halomethyl substituents bind with an affinity at least 50% that of estradiol; in the three atom alkyl series, the affinity declined markedly from propargyl (44%) and allyl (38%) to propyl (5%), suggestive of detailed steric constraints or a preference for unsaturation. The larger, more highly functionalized derivatives ranged in affinity from 0.1 - 7%, with the highest affinity binders being benzyl (5%) and 4-phenoxy-2(E)-butenyl (7%); most of the lowest affinity ones were the bulky fluorescent and photoreactive derivatives. Thus, the estrogen receptor has good tolerance for estradiol derivatives substituted at the 16.alpha.-position with nonpolar groups of moderate bulk; however, with groups of larger bulk, affinity is much lower and becomes highly dependent upon the polarity and detailed structure of the substituents.