Diarylpropionitrile (DPN) Enantiomers: Synthesis and Evaluation of Estrogen Receptor 尾-Selective Ligands

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• 作者：Vincent M. Carroll ; M. Jeyakumar ; Kathryn E. Carlson ; John A. Katzenellenbogen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 12, 2012
• 年：2012
• 卷：55
• 期：1
• 页码：528-537
• 全文大小：345K
• 年卷期：v.55,no.1(January 12, 2012)
• ISSN：1520-4804

文摘

Two estrogen receptor (ER) subtypes, ER伪 and ER尾, 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伪 vs ER尾. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ER尾 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尾 over ER伪, typically in the range of 80鈥?00-fold. Although the enantioselectivity is only modest (3鈥?-fold), the R-enantiomer is the higher affinity and more potent isomer. While ER尾 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尾 function.