TY - JOUR
T1 - Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists
AU - Inoue, Kazumi
AU - Urushibara, Ko
AU - Kanai, Misae
AU - Yura, Kei
AU - Fujii, Shinya
AU - Ishigami-Yuasa, Mari
AU - Hashimoto, Yuichi
AU - Mori, Shuichi
AU - Kawachi, Emiko
AU - Matsumura, Mio
AU - Hirano, Tomoya
AU - Kagechika, Hiroyuki
AU - Tanatani, Aya
N1 - Funding Information:
This work was partly supported by JSPS KAKENHI Grant Nos. 25460146 (to FS), No 22136013 (to HK) and 24590137 (to AT), JSPS Core-to-Core Program, A. Advanced Research Networks, and Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from Japan Agency for Medical Research and Development (AMED) . A.T. thanks The Naito Foundation for financial support.
Publisher Copyright:
© 2015 Elsevier Masson SAS.
PY - 2015/9/18
Y1 - 2015/9/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84939634322&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939634322&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2015.08.002
DO - 10.1016/j.ejmech.2015.08.002
M3 - Article
C2 - 26295173
AN - SCOPUS:84939634322
SN - 0223-5234
VL - 102
SP - 310
EP - 319
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 8038
ER -