Development of 6-arylcoumarins as nonsteroidal progesterone antagonists. Structure-activity relationships and fluorescence properties

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• 作者：Marie Kinoshita^a ; Mai Negishi^a ; Haruka Sakai^a ; Tomoya Hirano^b ; Shuichi Mori^b ; Shinya Fujii^b ; ^c ; Hiroyuki Kagechika^b ; Aya Tanatani^a ; ^{tanatani.aya@ocha.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Progesterone ; Antagonist ; Fluorescent ligand ; Coumarin
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5602-5610
• 全文大小：1262 K

文摘

Progesterone is involved in multiple physiological processes, including female reproduction, via binding to the progesterone receptor (PR). We have developed 6-arylcoumarins such as 5 and 6 as non-steroidal PR antagonists with receptor-binding-dependent fluorescence. In this study, we investigated the structure–activity relationships and fluorescence properties of coumarin derivatives bearing a heterocyclic aromatic moiety. Among these derivatives, 7c (IC₅₀: 34 nM) and 10b (IC₅₀: 24 nM) showed more potent PR-antagonistic activity than lead compounds 5 (IC₅₀: 500 nM) and 6 (IC₅₀: 65 nM) in alkaline phosphatase (AP) assay. Compound 9b showed solvent-dependent fluorescence intensity, exhibiting strong fluorescence in the presence of PR LBD only in buffer solution. On the other hand, 10b showed a solvent-dependent shift of the fluorescence maximum wavelength in the presence of PR LBD. These results indicate that 6-arylcoumarin will be a useful scaffold for PR antagonists and fluorescent probes targeting PR.