Synthesis, biological evaluation and molecular docking of 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs containing the piperazine moiety

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 20; pp. 115081 - 115088
• Main Authors: Chen, Hong, Zhang, Jingxiao, Hu, Peixin, Qian, Yuna, Li, Jing, Shen, Jianliang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2019; Elsevier
• Subjects: 4-Amino-2H-benzo[h]chromen-2-one analogs; Antagonistic activities; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Molecular docking; Pharmacology & Pharmacy; Physical Sciences; Prostate cancer; Science & Technology; Synthesis; 4-Amino-2H-benzo[h]chromen-2-one analogs; Synthesis; Antagonistic activities; Prostate cancer; Molecular docking; ANDROGEN RECEPTOR; ARYLPIPERAZINE DERIVATIVES; DESIGN; ANTIPROLIFERATIVE AGENTS; BREAST CANCER ACTIVITY; SYSTEMIC THERAPY; ANTITUMOR AGENTS; PROSTATE-CANCER; ANTAGONISTS; ENZALUTAMIDE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.115081

[Display omitted] •A novel of Amino-2H-benzo[h]chromen-2-one analogs was synthesized.•Antiproliferative and AR antagonist activity of Amino-2H-benzo[h]chromen-2-one analogs were investigated.•Some Amino-2H-benzo[h]chromen-2-one analogs exhibited strong biological activities against AR and LNCaP cells.•Molecular docking and SAR of Amino-2H-benzo[h]chromen-2-one analogs were also studied. Prostate cancer (PCa) is a major cause of cancer-related male death in worldwide. To develop of potential anti-prostate cancer agents, 22 kinds of 4-Amino-2H-benzo[h]chromen-2-one analogs were designed and synthesized as potent androgen receptor (AR) antagonist through rational drug modification leading to the discovery of a series of novel antiproliferative compounds. Analogs (3, 4, 5, 7, 8, 10, 11, 12, 16, 18, 21, 23, and 24) exhibited potent antagonistic potency against AR (inhibition >50%), and exhibited potent AR binding affinities as well as displayed the higher activities than finasteride toward LNCaP cells (AR-rich) versus PC-3 cells (AR-deficient). Moreover, the docking study suggested that the most potent antagonist 23 mainly bind to AR ligand binding pocket (LBP) site through Van der Waals’ force interactions. The structure-activity relationship (SAR) of these designed 4-Amino-2H-benzo[h]chromen-2-one analogs was rationally explored and discussed. Collectively, this work provides a potential lead compound for anticancer agent development related to prostate cancer therapy, and took a step forward towards the development of novel and improved AR antagonists.