Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers

Design, Synthesis, and Evaluation of New Mesenchymal–Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC50 value of 0.002 μM, compared to tepotinib (IC50 = 0.013 μM). M...

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Veröffentlicht in:Molecules (Basel, Switzerland) Switzerland), 2022-08, Vol.27 (17), p.5359
Hauptverfasser: Yao, Han, Ren, Yuanyuan, Yan, Jun, Liu, Jiadai, Hu, Jinhui, Yan, Ming, Li, Xingshu
Format: Artikel
Sprache:eng
Schlagworte:
AKT protein
Analysis
Apoptosis
c-Met inhibitors
cancer
Cancer therapies
Cell cycle
Cell lines
chiral compounds
Crizotinib
Embryonic development
FDA approval
G1 phase
Hydrogen
kinase
Kinases
Ligands
Mesenchyme
Metabolism
Signal transduction
Single crystals
Sodium
Stem cells
tepotinib
Tumors
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Zusammenfassung:A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC50 value of 0.002 μM, compared to tepotinib (IC50 = 0.013 μM). Mechanistic studies revealed that compound (R, S)-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound (R, S)-12a induced cellular apoptosis and cell cycle arrest at the G1 phase in a dose-dependent fashion.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27175359