Kotaro Ochiai

We 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 (IC 50 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 (IC 50 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.