Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore

• Main Authors: Hitomi Koga, Mai Negishi, Marie Kinoshita, Shinya Fujii, Shuichi Mori, Mari Ishigami-Yuasa, Emiko Kawachi, Hiroyuki Kagechika, Aya Tanatani
• Format: Article
• Language: English
• Published: MDPI AG 2020-08-01
• Series: International Journal of Molecular Sciences
• Subjects: prostate cancer; cell proliferation; coumarin; cis-amide
• Online Access: https://www.mdpi.com/1422-0067/21/15/5584
• ISSN: 1661-6596; 1422-0067

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (<b>2a</b>) and bicalutamide (<b>3</b>), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(<i>N</i>-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells. Coumarinamides with a secondary amide bond did not show inhibitory activity, but their <i>N</i>-methylated derivatives exhibited AR-antagonistic activity. Especially, <b>19b</b> and <b>31b</b> were more potent than the lead compound <b>7b</b>, which was comparable to hydroxyflutamide (<b>2b</b>). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a <i>trans</i>-amide bond, while the active <i>N</i>-methylated coumarinamides have a folded structure with a <i>cis</i>-amide bond, in which the two aromatic rings are placed face-to-face. Docking study suggested that this folded structure is important for binding to AR. Selected coumarinamide derivatives showed AR-antagonistic activity toward LNCaP cells with T877A AR, and they had weak progesterone receptor (PR)-antagonistic activity. The folded coumarinamide structure appears to be a unique pharmacophore, different from those of conventional AR antagonists.