Dataset Information

Synthesis and evaluation of 11β-(4-substituted phenyl) estradiol analogs: transition from estrogen receptor agonists to antagonists.

ABSTRACT:

Introduction

As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11β-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11β-(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 11β-aryl estradiol analogs or their potential as scaffolds for drug conjugation.

Methods

We prepared and characterized a series of 11β-(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 ERβ-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 ERα-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 11β-substituent than upon the nature of the terminal group

Conclusions

We have developed a synthetic strategy that provides facile access to potent 11β-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ERα-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11β-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 11β-aryl estradiol analogs as potential drug delivery systems and imaging agents.

SUBMITTER: Hanson RN

PROVIDER: S-EPMC3581310 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Publications

Synthesis and evaluation of 11β-(4-substituted phenyl) estradiol analogs: transition from estrogen receptor agonists to antagonists.

Hanson Robert N RN Hua Edward E Hendricks J Adam JA Labaree David D Hochberg Richard B RB

Bioorganic & medicinal chemistry 20120507 12

<h4>Introduction</h4>As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11β-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11β-(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 antagoni ...[more]

PMID: 22608920

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Dataset Information

Synthesis and evaluation of 11β-(4-substituted phenyl) estradiol analogs: transition from estrogen receptor agonists to antagonists.

Introduction

Methods

Results

Conclusions

Publications

Synthesis and evaluation of 11β-(4-substituted phenyl) estradiol analogs: transition from estrogen receptor agonists to antagonists.

Similar Datasets

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