Minutolo Filippo, Bellini Rosalba, Bertini Simone, Carboni Isabella, Lapucci Annalina, Pistolesi Letizia, Prota Giovanni, Rapposelli Simona, Solati Francesca, Tuccinardi Tiziano, Martinelli Adriano, Stossi Fabio, Carlson Kathryn E, Katzenellenbogen Benita S, Katzenellenbogen John A, Macchia Marco
Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Pisa, Italy.
J Med Chem. 2008 Mar 13;51(5):1344-51. doi: 10.1021/jm701396g. Epub 2008 Feb 13.
Salicylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A ring that is characteristic of most estrogen receptor (ER) ligands. Monoaryl-substituted salicylaldoximes were obtained by replacing the phenol moiety (ring A) of the ERbeta pharmacophore with the pseudocycle A' ring, which has previously been shown to behave as a bioequivalent of phenols in nonselective ER ligands. In this series, small substituents (CH 3, CN, Cl) were introduced into the central phenyl scaffold. An efficient sequential halogen-selective double cross-coupling reaction was developed for the synthesis of the methyl-substituted ER ligand. The measured ERbeta affinity proved to be very sensitive to the effect of central core substituents. The binding affinities of the compounds herein reported were in good agreement with the results of computational docking analysis. The chloro-substituted derivative showed the highest beta affinity and selectivity, and it also proved to be an ERbeta partial agonist with an EC 50 of 11 nM.
水杨醛肟具有一个氢键连接的假环A'环，取代了大多数雌激素受体（ER）配体所特有的典型酚类A环。单芳基取代的水杨醛肟是通过用假环A'环取代ERβ药效基团的酚部分（A环）而获得的，此前已证明该假环在非选择性ER配体中表现为酚的生物等效物。在该系列中，小取代基（CH₃、CN、Cl）被引入到中心苯基骨架中。开发了一种高效的顺序卤素选择性双交叉偶联反应来合成甲基取代的ER配体。测得的ERβ亲和力被证明对中心核心取代基的影响非常敏感。本文报道的化合物的结合亲和力与计算对接分析的结果非常吻合。氯取代衍生物显示出最高的β亲和力和选择性，并且还被证明是一种EC₅₀为11 nM的ERβ部分激动剂。
