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

Abstract

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide (2a) and bicalutamide (3), 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-(N-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 N-methylated derivatives exhibited AR-antagonistic activity. Especially, 19b and 31b were more potent than the lead compound 7b, which was comparable to hydroxyflutamide (2b). Conformational analysis showed that the inactive coumarinamides with a secondary amide bond have an extended structure with a trans-amide bond, while the active N-methylated coumarinamides have a folded structure with a cis-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.

• Authors: Hitomi Koga, Mai Negishi, Marie Kinoshita, Shinya Fujii, Shuichi Mori, Mari Ishigami-Yuasa, Emiko Kawachi, Hiroyuki Kagechika, Aya Tanatani
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 15 (Aug 04 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32759847 (Publication Type: Journal Article)

Chemical References

• Androgen Receptor Antagonists
• Androgens
• Coumarins
• Nonsteroidal Anti-Androgens
• Receptors, Androgen
• hydroxyflutamide
• Flutamide
• Prostate-Specific Antigen

Topics

• Androgen Receptor Antagonists (chemistry, pharmacology)
• Androgens (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Coumarins (chemistry, pharmacology)
• Flutamide (analogs & derivatives, chemistry, pharmacology)
• Humans
• Male
• Molecular Structure
• Mutation
• Nonsteroidal Anti-Androgens (chemistry, pharmacology)
• Prostate-Specific Antigen (genetics)
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Androgen (drug effects, genetics)