Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists

Kazumi Inoue, Ko Urushibara, Misae Kanai, Kei Yura, Shinya Fujii, Mari Ishigami-Yuasa, Yuichi Hashimoto, Shuichi Mori, Emiko Kawachi, Mio Matsumura, Tomoya Hirano, Hiroyuki Kagechika, Aya Tanatani

研究成果: Article査読

15 被引用数 (Scopus)

抄録

The androgen receptor (AR) plays important roles in multiple physiological functions, including differentiation, growth, and maintenance of male reproductive organs, and also has effects on hair and skin. In this paper, we report the synthesis of nonsteroidal AR antagonists having a 4-benzyl-1-(2H)-phthalazinone skeleton. Among the synthesized compounds, 11c with two ortho-substituents on the phenyl group potently inhibited SC-3 cell proliferation (IC50: 0.18 μM) and showed high wt AR-binding affinity (IC50: 10.9 μM), comparable to that of hydroxyflutamide (3). Compound 11c also inhibited proliferation of LNCaP cells containing T877A-mutated AR. Docking study of 11c with the AR ligand-binding domain indicated that the benzyl group is important for the antagonism. These phthalazinone derivatives may be useful for investigating potential clinical applications of AR antagonists.

本文言語English
論文番号8038
ページ(範囲)310-319
ページ数10
ジャーナルEuropean Journal of Medicinal Chemistry
102
DOI
出版ステータスPublished - 2015 9 18
外部発表はい

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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