CONFORMATIONAL EFFECTS ON RETINOID RECEPTOR SELECTIVITY .1. EFFECT OF 9-DOUBLE BOND GEOMETRY ON RETINOID-X RECEPTOR ACTIVITY
CONFORMATIONAL EFFECTS ON RETINOID RECEPTOR SELECTIVITY .1. EFFECT OF 9-DOUBLE BOND GEOMETRY ON RETINOID-X RECEPTOR ACTIVITY
复制标题
DOI：
10.1021/jm00070a003
复制
发表时间：
1993-09-03
影响因子：
7.3
通讯作者：
DAWSON, MI
中科院分区：
文献类型：
--
作者：
JONG, L;LEHMANN, JM;DAWSON, MI
一个主要的挑战是开发具有选择性生物活性的类维生素A。近年来，对类维生素A反应机制的研究表明，类维生素A激活两类核受体蛋白，视黄酸受体（RAR）和类维生素A X受体（RXR）。在这里，我们分析了一系列（E）-和（Z）-芪羧酸的活性，用于RAR和RXR-α的基因转录激活，以确定受体激活的最佳药效团。所获得的数据表明，RAR和RXR反应途径可以通过使用适当的配体分离。通过实验和理论方法研究了（Z）-4-[2-（5，6，7，8-四氢-5，5，8，8-四甲基-2-萘基）丙烯-1-基]苯甲酸和（Z）-4-[1-（5，6，7，8-四氢-5，5，8，8-四甲基-2-萘基）丙烯-2-基]苯甲酸的构象，以确定后者特异性激活类视色素RXR的适当构象。在非无水条件下，用钯（0）催化的芳基溴-芳基硼酸偶联反应在具有RXR活性的维甲酸类化合物2 '-（5，6，7，8-四氢-5，5，8，8-四甲基-2-萘基）联苯-4-羧酸中构建了一个联芳基键。
A major challenge is the development of retinoids with selective biological activities. Recently, studies on retinoid response mechanisms indicate that retinoids activate two classes of nuclear receptor proteins, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Here, we analyze the activity of a series of (E)- and (Z)-stilbenecarboxylic acids for gene transcriptional activation of the RARs and RXR-alpha to determine the optimum pharmacophore for receptor activation. The data obtained indicate that RAR and RXR response pathways can be separated by using the appropriate ligand. The conformations of (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propen-1-yl]benzoic acid and (Z)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propen-2-yl]benzoic acid were examined by experimental and theoretical methods to establish the appropriate conformation of the latter that specifically activated the retinoid RXR. A palladium(0)-catalyzed aryl bromide-arylboronic acid coupling under nonanhydrous conditions was used to construct a biaryl bond in the conformationally restricted retinoid 2'-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)biphenyl-4-carboxylic acid, which had RXR activity.