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

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number8038
Pages (from-to)310-319
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume102
DOIs
Publication statusPublished - 2015 Sep 18
Externally publishedYes

Fingerprint

Androgen Receptor Antagonists
Androgen Receptors
Derivatives
Inhibitory Concentration 50
Cell Proliferation
Cell proliferation
Skeleton
Hair
Skin
Maintenance
Ligands
Growth

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists. / Inoue, Kazumi; Urushibara, Ko; Kanai, Misae; Yura, Kei; Fujii, Shinya; Ishigami-Yuasa, Mari; Hashimoto, Yuichi; Mori, Shuichi; Kawachi, Emiko; Matsumura, Mio; Hirano, Tomoya; Kagechika, Hiroyuki; Tanatani, Aya.

In: European Journal of Medicinal Chemistry, Vol. 102, 8038, 18.09.2015, p. 310-319.

Research output: Contribution to journalArticle

Inoue, K, Urushibara, K, Kanai, M, Yura, K, Fujii, S, Ishigami-Yuasa, M, Hashimoto, Y, Mori, S, Kawachi, E, Matsumura, M, Hirano, T, Kagechika, H & Tanatani, A 2015, 'Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists', European Journal of Medicinal Chemistry, vol. 102, 8038, pp. 310-319. https://doi.org/10.1016/j.ejmech.2015.08.002
Inoue, Kazumi ; Urushibara, Ko ; Kanai, Misae ; Yura, Kei ; Fujii, Shinya ; Ishigami-Yuasa, Mari ; Hashimoto, Yuichi ; Mori, Shuichi ; Kawachi, Emiko ; Matsumura, Mio ; Hirano, Tomoya ; Kagechika, Hiroyuki ; Tanatani, Aya. / Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists. In: European Journal of Medicinal Chemistry. 2015 ; Vol. 102. pp. 310-319.
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AU - Ishigami-Yuasa, Mari

AU - Hashimoto, Yuichi

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