二氢月桂酸脱氢酶
化学
胡椒碱
癌细胞
癌症
生物化学
脱氢酶
酶
癌症研究
遗传学
生物
有机化学
作者
Jianfei Zhang,Li-Hong Hong,Shiying Fan,Ling Zhu,Zhan‐Peng Yu,Chen Chen,Lingyi Kong,Jian‐Guang Luo
标识
DOI:10.1016/j.bioorg.2024.107594
摘要
Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.
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