Synthesis and evaluation of 11尾-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists

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• 作者：Robert N. Hanson^a ; ^{r.hanson@neu.edu} ; Edward Hua^a ; J. Adam Hendricks^a ; David Labaree^b ; Richard B. Hochberg^b
• 关键词：Steroidal anti-estrogens ; Estrogen receptor ; Synthesis ; Agonist ; Antagonist ; Conformational analysis
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 June, 2012
• 卷：20
• 期：12
• 页码：3768-3780
• 文件大小：750 K

摘要

Introduction

As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11尾-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11尾-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11尾-aryl estradiol analogs or their potential as scaffolds for drug conjugation.

Methods

We prepared and characterized a series of 11尾-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ER尾-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists.

Results

The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ER伪-LBD, ranging from 13-83%that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11尾-substituent than upon the nature of the terminal group

Conclusions

We have developed a synthetic strategy that provides facile access to potent 11尾-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER伪-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11尾-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11尾-aryl estradiol analogs as potential drug delivery systems and imaging agents.