Design and Synthesis of 4‑(4-Benzoylaminophenoxy)phenol
Derivatives As Androgen Receptor Antagonists
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Abstract
We
report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol
derivatives that bind to the androgen receptor (AR) ligand-binding
domain and exhibit potent androgen-antagonistic activity. Compound <b>22</b> is one of the most potent of these derivatives, inhibiting
the dihydrotestosterone-promoted growth of SC-3 cell line bearing
wild-type AR (IC<sub>50</sub> 0.75 μM), LNCaP cell line bearing
T877A-mutated AR (IC<sub>50</sub> 0.043 μM), and 22Rv1 cell
line bearing H874Y-mutated AR (IC<sub>50</sub> 0.22 μM). Structure–activity
relationship studies confirmed that the pharmacophore of these novel
AR antagonists is distinct from the nitro- or cyano-substituted anilide
substructure of other nonsteroidal AR antagonists. This novel pharmacophore
is expected to provide a basis for designing new antiprostate cancer
agents