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

doi:10.1016/j.ejmech.2015.08.002

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

Eur J Med Chem. 2015 Sep 18:102:310-9. doi: 10.1016/j.ejmech.2015.08.002. Epub 2015 Aug 6.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
² Center for Informational Biology, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan; National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
³ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 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 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
⁵ Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁶ 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: 26295173
DOI: 10.1016/j.ejmech.2015.08.002

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.

Keywords: Androgen receptor; Antagonist; Phthalazinone; Prostate cancer.

Publication types

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

MeSH terms

Androgen Receptor Antagonists / chemical synthesis*
Androgen Receptor Antagonists / chemistry
Androgen Receptor Antagonists / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Male
Mice
Models, Molecular
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Receptors, Androgen / metabolism*
Structure-Activity Relationship

Substances

4-(2,6-dichlorophenyl)methyl-1-(2H)-phthalazinone
Androgen Receptor Antagonists
Antineoplastic Agents
Phthalazines
Receptors, Androgen