Design, Synthesis, Antitumor Activity Evaluation, and Molecular Dynamics Simulation of Some 2-Aminopyrazine Derivatives.
Curr Comput Aided Drug Des
; 2024 Mar 12.
Article
em En
| MEDLINE
| ID: mdl-38485684
ABSTRACT
OBJECTIVE:
Cancer poses a great threat to human health, and effective drugs to treat it are always needed. Several compounds containing a 2-aminopyrazine framework have been identified as antitumor agents with SHP2 inhibition activities. This current work aimed to search for more potent novel compounds possessing a 2-aminopyrazine moiety with antitumor activities.METHODS:
A series of 12 novel 2-aminopyrazine derivatives was synthesized, and their structures were confirmed by spectroscopic techniques. The inhibitory activities of all the synthesized compounds against MDA-MB-231 and H1975 cancer cell lines were evaluated by an MTT assay. The most potent compound 3e was analyzed by flow cytometry. Subsequently, computational studies were performed to investigate the possible antitumor mechanisms of compound 3e.RESULTS:
The results indicated that compound 3e exhibited potent antitumor activities with IC50 values of 11.84±0.83µM against H1975 cells and 5.66±2.39µM against MDA-MB-231 cells, which were more potent than the SHP2 inhibitor GS493 (IC50 = 19.08±1.01 µM against H1975 cells and IC50 = 25.02±1.47 µM against MDA-MB-231 cells). Further analysis by flow cytometry demonstrated that compound 3e induced cell apoptosis in H1975 cells. The results of the molecular docking and MD simulations, including RMSD, RMSF, PCA, DCCM and binding energy and decomposition analyses, revealed that compound 3e probably selectively inhibited SHP2.CONCLUSION:
A new compound having a 2-aminopyrazine substructure with potent inhibitory activities against the H1975 and MDA-MB-231 cancer cells was obtained, meriting further investigation as an antitumor drug.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Curr Comput Aided Drug Des
Assunto da revista:
FARMACOLOGIA
/
INFORMATICA MEDICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China