Affiliation:
1. Institute of Biomaterials and Bioengineering Tokyo Medical and Dental University 2-3-10 Kanda-Surugadai Chiyoda-ku Tokyo 101-0062 Japan
Abstract
AbstractWe previously identified nitrophenylferrocenes and cyanophenylferrocenes as promising lead structures of novel androgen receptor (AR) antagonists, based on the structural similarity between ferrocene and the steroidal skeleton. In the present research, we explored the structure‐activity relationship (SAR) of phenylferrocene derivatives. Introduction of a hydrophobic substituent such as a chlorine atom at the 2‐position or 3‐position of phenylferrocene derivatives significantly increased the antagonistic activity toward wild‐type AR, and among the synthesized compounds, 3‐chloro‐4‐cyanophenylferrocene (29) exhibited the most potent anti‐proliferative activity toward the androgen‐dependent growth of SC‐3 cells expressing wild‐type AR (IC50 14 nM). Like conventional antiandrogens such as hydroxyflutamide, the major active metabolite of flutamide, compound 29 exhibited agonistic activity toward T877A‐AR, a mutant AR expressed in human prostate cancer cell line LNCaP. Notably, however, the 2‐chloro isomer 27 showed potent antagonistic activity toward wild‐type AR (IC50 49 nM) and also exhibited antagonistic activity toward T877A‐AR. Our SAR data should prove helpful for the development of new‐generation AR antagonists based on phenylferrocene as candidate agents to treat drug‐resistant prostate cancer.
Funder
Takeda Science Foundation
Hoansha Foundation
Research Center for Biomedical Engineering
Japan Agency for Medical Research and Development
Cited by
1 articles.
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