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

Marie Kinoshita; Mai Negishi; Haruka Sakai; Tomoya Hirano; Shuichi Mori; Shinya Fujii; Hiroyuki Kagechika; Aya Tanatani

doi:10.1016/j.bmc.2016.09.020

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

Bioorg Med Chem. 2016 Nov 1;24(21):5602-5610. doi: 10.1016/j.bmc.2016.09.020. Epub 2016 Sep 12.

Authors

Marie Kinoshita¹, Mai Negishi¹, Haruka Sakai¹, Tomoya Hirano², Shuichi Mori², Shinya Fujii³, Hiroyuki Kagechika², Aya Tanatani⁴

Affiliations

¹ Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
² School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
³ School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁴ Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan. Electronic address: tanatani.aya@ocha.ac.jp.

PMID: 27665178
DOI: 10.1016/j.bmc.2016.09.020

Abstract

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: 34nM) and 10b (IC₅₀: 24nM) showed more potent PR-antagonistic activity than lead compounds 5 (IC₅₀: 500nM) and 6 (IC₅₀: 65nM) 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.

Keywords: Antagonist; Coumarin; Fluorescent ligand; Progesterone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Fluorescence*
Humans
Molecular Structure
Progesterone / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Coumarins
Progesterone