Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells

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.