期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 102, 期 -, 页码 310-319出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.08.002
关键词
Androgen receptor; Antagonist; Phthalazinone; Prostate cancer
资金
- JSPS [25460146, 22136013, 24590137]
- Japan Agency for Medical Research and Development (AMED)
- Naito Foundation
- Grants-in-Aid for Scientific Research [24590137, 22136013, 15K08019, 25460146] Funding Source: KAKEN
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 mu M) and showed high wt AR-binding affinity (IC50: 10.9 mu M), 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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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