Hanson Robert N, Lee Choon Young, Friel Carolyn J, Dilis Robert, Hughes Alun, DeSombre Eugene R
Departments of Chemistry and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA.
J Med Chem. 2003 Jul 3;46(14):2865-76. doi: 10.1021/jm0205806.
As part of our program to develop probes for the hormone binding domain of the estrogen receptor alpha (ERalpha), we prepared a series of 4-para-substituted phenylvinyl estradiol derivatives using a combination of solution and solid-phase Pd(0)-catalyzed methods. The compounds 5a-j were evaluated for their binding affinity using the ERalpha hormone binding domain (HDB) isolated from transfected BL21 cells. The results indicated that although the new compounds were somewhat lower in relative binding affinity (RBA at 25 degrees C is 1-60%) than estradiol (100%), most had higher affinity than the unsubstituted parent phenylvinyl estradiol (RBA = 9%). Because the substituents did not generate a structure-activity relationship directly based on physicochemical properties, the series was evaluated using molecular modeling and molecular dynamics to determine key interactions between the ligand, especially the para substituent, and the protein. The results suggest that the observed relative binding affinities are directly related to the calculated binding energies and that amino acids juxtaposed to the para position play a significant but not dominant role in binding. In conclusion, we have identified the 17alpha-E-(4-substituted phenyl)vinyl estradiols as a class of ligands that retain significant affinity for the ERalpha-HBD. In particular, 4-substitution tends to increase receptor affinity compared to the unsubstituted analogue, as exemplified by 5e (4-COCH(3)), which had the highest RBA value (60%) of the series. Palladium(0)-catalyzed coupling reactions on solid support or in solution using suitably substituted iodo arenes and 17alpha-E-tributylstannylvinyl estradiols offer a flexible approach to their preparation. Molecular modeling studies of the receptor suggest that there exists additional ligand accessible regions within the ERalpha-HBD to generate interactions that may enhance receptor affinity or modify efficacy in developing new therapeutic agents. Studies to undertake modification in the properties and/or position of the aryl substituents in subsequent series to further define that role are in progress.
作为我们开发雌激素受体α（ERα）激素结合域探针计划的一部分，我们使用溶液和固相钯（0）催化方法相结合的方式制备了一系列4-对位取代苯乙烯基雌二醇衍生物。使用从转染的BL21细胞中分离出的ERα激素结合域（HDB）评估化合物5a-j的结合亲和力。结果表明，尽管新化合物的相对结合亲和力（25℃下的RBA为1-60%）比雌二醇（100%）略低，但大多数化合物的亲和力高于未取代的母体苯乙烯基雌二醇（RBA = 9%）。由于取代基并未直接基于物理化学性质产生构效关系，因此使用分子建模和分子动力学对该系列进行评估，以确定配体尤其是对位取代基与蛋白质之间的关键相互作用。结果表明，观察到的相对结合亲和力与计算出的结合能直接相关，并且与对位相邻的氨基酸在结合中起重要但非主导作用。总之，我们已确定17α-E-（4-取代苯基）乙烯基雌二醇为一类对ERα-HBD保留显著亲和力的配体。特别是，与未取代的类似物相比，4-取代倾向于增加受体亲和力，如5e（4-COCH(3)）所示，它是该系列中RBA值最高（60%）的化合物。使用适当取代的碘代芳烃和17α-E-三丁基锡基乙烯基雌二醇在固相载体上或溶液中进行钯（0）催化偶联反应，为其制备提供了一种灵活的方法。对受体的分子建模研究表明，在ERα-HBD内存在额外的配体可及区域，以产生可能增强受体亲和力或在开发新治疗剂时改变效力的相互作用。正在进行研究以对后续系列中芳基取代基的性质和/或位置进行修饰，以进一步确定该作用。
