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Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor ?-selective ligands.

ABSTRACT: Two estrogen receptor (ER) subtypes, ER? and ER?, mediate the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activate these subtypes differentially, have proved to be useful in elucidating which actions of estrogens proceed through ER? vs ER?. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ER? selective ligand that we developed, is a chiral molecule, but it has been studied almost exclusively as the racemic mixture (rac-DPN, 1). Herein we report the development of an efficient enantioselective synthesis of the two isomers, R-DPN (3) and S-DPN (2), and we have compared the in vitro ligand binding affinities, coactivator binding affinities, recruitment potencies, and cellular transcriptional potencies of these isomers. Both enantiomers show a very high affinity and potency preference for ER? over ER?, typically in the range of 80-300-fold. Although the enantioselectivity is only modest (3-4-fold), the R-enantiomer is the higher affinity and more potent isomer. While ER? can be effectively and selectively stimulated by rac-DPN or by either R-DPN or S-DPN, R-DPN might be the preferred member of this isomeric series for biological studies of ER? function.

SUBMITTER: Carroll VM

PROVIDER: S-EPMC3381613 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor β-selective ligands.

Carroll Vincent M VM Jeyakumar M M Carlson Kathryn E KE Katzenellenbogen John A JA

Journal of medicinal chemistry 20111214 1

Two estrogen receptor (ER) subtypes, ERα and ERβ, mediate the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activate these subtypes differentially, have proved to be useful in elucidating which actions of estrogens proceed through ERα vs ERβ. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ERβ selective ligand that we developed, is a chiral molecule, but it has been ...[more]

PMID: 22122563

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Project description:AimTo discover novel ligands of estrogen receptor (ER) β using pharmacophore mapping and structure-based screening.MethodsA computer-aided strategy combining pharmacophore mapping and structure-based screening was used to screen the Maybridge and Enamine databases. Yeast two-hybrid (Y2H) assay was used to detect the activity and selectivity of the chosen compounds. The transcriptional activities of the chosen compounds were demonstrated with luciferase reporter assays. The anti-proliferative effects of ER antagonists against MCF-7 and MDA-MB-231 breast cancer cells were examined using MTT assay, and the mechanisms of action were analyzed with flow cytometry analysis and Western blotting.ResultsThrough in silico screen, 95 compounds were chosen for testing in Y2H assay, which led to 20 potent ligands, including 10 agonists, 8 antagonists and 2 partial agonists with EC50 or IC50 values at μmol/L. Furthermore, 6 agonists exhibited absolute selectivity for ERβ, and 3 agonists showed higher selectivity for ERβ. The agonists 1g and 1h (10, 25, and 50 μmol/L) dose-dependently increased ER transcriptional activities, whereas the antagonists 2a and 2d (10, 25, and 50 μmol/L) caused dose-dependent inhibition on the activities. The antagonists and partial agonists at 100 μmol/L suppressed the proliferation of ERα positive MCF-7 cells and ERβ positive MDA-MB-231 cells, but were more effective against MDA-MB-231 cells. Treatment of MDA-MB-231 cells with antagonists 2a and 2d (25 and 50 μmol/L) dose-dependently increased the population of cells in the S phase. Both 2a and 2d treatment dose-dependently decreased the expression levels of cyclin A and CDK2. Meanwhile, the downregulation of cyclin E was only caused by 2d, while 2a treatment did not cause significant changes in the protein levels of cyclin E.ConclusionThe selective ligands discovered in this study are promising drug candidates to be used as molecular probes to explore the differences between ERα and ERβ.

Dataset Information

Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor ?-selective ligands.

Publications

Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor β-selective ligands.

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