3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis.
Bioorg Chem
; 114: 105101, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-34175723
ABSTRACT
Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinoxalinas
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Proteína p53 Supresora de Tumor
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Fosfatidilinositol 3-Quinasas
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Inhibidores Enzimáticos
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Proteínas Proto-Oncogénicas c-akt
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Serina-Treonina Quinasas TOR
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2021
Tipo del documento:
Article