Minutolo Filippo, Antonello Michela, Bertini Simone, Rapposelli Simona, Rossello Armando, Sheng Shubin, Carlson Kathryn E, Katzenellenbogen John A, Macchia Marco
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126, Pisa, Italy.
Bioorg Med Chem. 2003 Apr 3;11(7):1247-57. doi: 10.1016/s0968-0896(02)00640-5.
An effective, unprecedented replacement of the prototypical phenolic 'A-ring' of estrogens with an oxime and a hydroxy-moiety of the salicylaldoxime derivative 3,4-diphenyl-substituted (1a) opened the way to study structure-activity relationships of a new class of estrogen receptor (ER)-ligands. Herein, we present a study of the ER binding properties and transcriptional activities of analogues of 3,4-diphenylsalicylaldoxime (1a). The introduction of p-OH and p-OMe groups on the phenyl substituents of 1a, as in compounds 1b-g, results in unique structure-activity profiles. The preparation of the hetero-disubstituted compounds (1b-e) was accomplished by a sequential introduction of different 3- and 4-aryl groups, obtained by exploiting the different reactivity of the bromine versus chlorine substituents on the precursor, 2-bromo-3-chloronitrobenzene (5), in the palladium-catalyzed cross-coupling reactions. The results of the biological tests show that the introduction of one hydroxy-group on the 3-phenyl substituent of the lead compound 1a improved the binding affinity on ERbeta (1c), whereas the introduction of the same group on the 4-phenyl substituent of 1a gave a compound (1e) with better affinity properties on ERalpha. The introduction of two hydroxyl groups in the para-position of both phenyl substituents of 1a, as in 1g, lowered the binding on both receptor subtypes. In transcription assays, the ERalpha agonist character of this class of ligands is enhanced by the presence of a p-hydroxy or p-methoxy in the 'distal' phenyl ring, whereas substitution on the other phenyl ring does not substantially modify the partial agonist character of 1a. Thus, results from the binding and transcription assays illustrate that this class of ER ligands has a distinct structure-activity profile on the two ER subtypes, being potent nearly full agonists on ERalpha and weak, partial antagonists on ERbeta.
用肟和3,4 - 二苯基取代的水杨醛肟衍生物（1a）的羟基部分有效且前所未有的取代雌激素的原型酚类“A环”，为研究一类新型雌激素受体（ER）配体的构效关系开辟了道路。在此，我们展示了对3,4 - 二苯基水杨醛肟（1a）类似物的ER结合特性和转录活性的研究。在1a的苯基取代基上引入对羟基和对甲氧基，如化合物1b - g中所示，产生了独特的构效关系。通过利用前体2 - 溴 - 3 - 氯硝基苯（5）上溴与氯取代基在钯催化交叉偶联反应中的不同反应性，依次引入不同的3 - 和4 - 芳基，完成了杂二取代化合物（1b - e）的制备。生物学测试结果表明，在先导化合物1a的3 - 苯基取代基上引入一个羟基提高了对ERβ的结合亲和力（1c），而在1a的4 - 苯基取代基上引入相同基团得到了对ERα具有更好亲和力特性的化合物（1e）。在1a的两个苯基取代基的对位引入两个羟基，如在1g中，降低了对两种受体亚型的结合。在转录测定中，“远端”苯环中存在对羟基或对甲氧基增强了这类配体的ERα激动剂特性，而在另一个苯环上的取代基本上不改变1a的部分激动剂特性。因此，结合和转录测定的结果表明，这类ER配体在两种ER亚型上具有独特的构效关系，对ERα是强效的近乎完全激动剂，对ERβ是弱的部分拮抗剂。
