Discovery of novel NF-кB inhibitor based on scaffold hopping: 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine.
Eur J Med Chem
; 198: 112366, 2020 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-32371335
ABSTRACT
NF-κB is a key signaling pathway molecule linking hepatoma and chronic inflammation. Inhibition of NF-κB activation can alleviate inflammation, and promote hepatoma cell apoptosis. In this study, a series of fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 31-57) were synthesized from 3,5-bis(arylidene)-4-piperidones (BAPs, 4-30) based on scaffold hopping. We successfully discovered the most potent 43 substituted by electron-withdrawing substitutes (3-F and 4-CF3) exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 43 induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF-κB activation by suppressing LPS-induced phosphorylation levels of p65, IκBα and Akt, and by indirectly suppressing MAPK signaling, and by inhibiting the nuclear translocation of NF-κB induced by TNF-α or LPS. Docking analysis verified simulated 43 could reasonably bind to the active site of Bcl-2, p65 and p38 proteins. This compound, as a novel NF-κB inhibitor, also demonstrated both anti-inflammatory and anti-hepatoma activities, warranting its further development as a potential multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.
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MEDLINE
Assunto principal:
Pirimidinas
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NF-kappa B
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Carcinoma Hepatocelular
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Inflamação
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Neoplasias Hepáticas
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Anti-Inflamatórios
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Antineoplásicos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article