Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.
Bioorg Chem
; 150: 107594, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-38941701
ABSTRACT
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Ensaios de Seleção de Medicamentos Antitumorais
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Proliferação de Células
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Alcaloides
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Inibidores Enzimáticos
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Benzodioxóis
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Alcamidas Poli-Insaturadas
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Ferroptose
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Di-Hidro-Orotato Desidrogenase
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Antineoplásicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article