Data Sheet 1_Synthesis, bioactivity, and molecular docking studies: novel arylpiperazine derivatives as potential new-resistant AR antagonists.docx

The majority of patients with androgen-dependent prostate cancer (PCa) develop resistance to hormone therapy after approximately 18–24 months of androgen deprivation therapy treatment. During this process, PCa cells progressively lose their sensitivity to androgens and evolve into castration-resistant prostate cancer leading to uncontrolled tumor growth and ultimately the failure of endocrine therapy. To develop potential anti-prostate cancer agents, in this study, we identified a novel ether-type arylpiperazine derivative as a potent androgen receptor (AR) antagonist, uncovering a series of effective antiproliferative compounds. The derivatives (7, 11, 17, 19, 20, 21, 22, 23, and 24) demonstrated strong cytotoxicity against cancer cells, with 17, 19, 20, and 23 showing significant androgen receptor antagonistic activity (Inhibition% >60) and robust AR binding affinities. The structure-activity relationship (SAR) of these developed derivatives was discussed based on data. Docking study suggested that the compound 19 mainly bind to AR ligand binding pocket site through Van der Waals’ force interactions. This research presents a promising lead compound for developing anticancer agents targeting prostate cancer therapy.