Synthesis, bioactivity, and molecular docking of novel arylpiperazine derivatives as potential AR antagonists

Yueheng Qi; Hong Chen; Shijin Chen; Jianliang Shen; Jingguo Li

doi:10.3389/fchem.2022.947065

Synthesis, bioactivity, and molecular docking of novel arylpiperazine derivatives as potential AR antagonists

Front Chem. 2022 Aug 15:10:947065. doi: 10.3389/fchem.2022.947065. eCollection 2022.

Authors

Yueheng Qi^{1

2}, Hong Chen², Shijin Chen², Jianliang Shen³, Jingguo Li¹

Affiliations

¹ Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
² Luoyang Key Laboratory of Organic Functional Molecules, College of Food and Drug, Luoyang Normal University, Luoyang, Henan, China.
³ School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Abstract

Prostate cancer is one of the malignant tumors and the second most common malignant tumor in men. Clinically used androgen receptor (AR)-targeted drugs can antagonize androgen and inhibit tumor growth, but these drugs can cause serious resistance problems. To develop novel AR antagonists, 22 kinds of arylpiperazine derivatives were designed and synthesized, and the derivatives 5, 8, 12, 19, 21, 22, 25, and 26 not only showed strong antagonistic potency (>55% inhibition) and binding affinities (IC₅₀ <3 μM) to AR, but also showed stronger inhibitory activity to LNCaP cells versus PC-3 cells. Among them, derivative 21 exhibited the highest binding affinity for AR (IC₅₀ = 0.65 μM) and the highest antagonistic potency (76.2% inhibition). Docking studies suggested that the derivative 21 is primarily bound to the AR-LBP site by the hydrophobic interactions. Overall, those results provided experimental methods for developing novel arylpiperazine derivatives as potent AR antagonists.

Keywords: antagonistic activity; binding affinities; molecular docking; prostate cancer; synthesis.