The androgen receptor (AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide (3a) and bicalutamide (4), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer. We previously reported a novel (benzoylaminophenoxy)phenol derivative 10a, which is structurally distinct from conventional AR antagonists. Here, we systematically examined the structure-activity relationship of (benzoylaminophenoxy)phenol derivatives on the inhibitory activity on the prostate cancer cell proliferations. We found that the 4-[4-(benzoylamino)phenoxy]phenol backbone is important for anti-prostate cancer activity. Introduction of a small substituent at the 2 position of the central benzene ring (B ring) increases the activity. Among the synthesized compounds, 19a and 19b exhibited the most potent inhibitory activity toward dihydrotestosterone-induced proliferation of several androgen-dependent cell lines, SC-3 (wild-type AR), LNCaP (T877A AR), and 22Rv1 (H874Y AR), but interestingly also inhibited proliferation of AR-independent PC-3 cells. These compounds, which have a different pharmacophore from conventional AR antagonists, are promising drug candidates for the treatment of prostate cancer.
Keywords: Cell proliferation; Pharmacophore; Phenoxyphenol; Prostate cancer.
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