Synthesis and biological evaluation of 4-phenoxy-phenyl isoxazoles as novel acetyl-CoA carboxylase inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Xin Wu¹  Tonghui Huang¹  Yongbo Yu¹ 

[1] Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University;

关键词: acetyl-coa carboxylase;    antitumor;    docking;    cell cycle;    apoptosis;   

DOI  :  10.1080/14756366.2021.1936514

来源: DOAJ

【 摘 要 】

Acetyl-CoA carboxylase (ACC) is a crucial enzyme in fatty acid metabolism, which plays a major role in the occurrence and development of certain tumours. Herein, one potential ACC inhibitor (6a) was identified through high-throughput virtual screening (HTVS), and a series of 4-phenoxy-phenyl isoxazoles were synthesised for structure-activity relationship (SAR) studies. Among these compounds, 6g exhibited the most potent ACC inhibitory activity (IC50=99.8 nM), which was comparable to that of CP-640186. Moreover, the antiproliferation assay revealed that compound 6l exhibited the strongest cytotoxicity, with IC50 values of 0.22 µM (A549), 0.26 µM (HepG2), and 0.21 µM (MDA-MB-231), respectively. The preliminary mechanistic studies on 6g and 6l suggested that the compounds decreased the malonyl-CoA levels, arrested the cell cycle at the G0/G1 phase, and induced apoptosis in MDA-MB-231 cells. Overall, these results indicated that the 4-phenoxy-phenyl isoxazoles are potential for further study in cancer therapeutics as ACC inhibitors.

【 授权许可】

Unknown