Anticancer Activities of Tetrasubstituted Imidazole-Pyrimidine-Sulfonamide Hybrids as Inhibitors of EGFR Mutants.
Eman M AlghamdiZahra M AlamshanyMohamed A El HamdEhab S TaherMohammed Farrag El-BehairyPhilip L NorcottAdel A MarzoukPublished in: ChemMedChem (2023)
A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores has been synthesized and evaluated for their anticancer activities. In-vitro screening of these hybrids against a full 60-cell-line panel at a single dose of 10 μM showed significant growth inhibition of up to 95 %. The most active compound showed in-vitro anticancer activities against (i) abnormal HER2 and (ii) two mutants for EGFR. Apoptotic gene expression revealed that lead compounds induced MCF-7 cell line apoptosis together with considerable change in the Bax/Bcl-2 expression ratio. One lead compound led to a significant cell-cycle S-phase arrest, while another blocked the cell cycle at G1/S-phase causing the accumulation of cells. Docking analysis of these two hybrids adopted the orientation and binding interactions with a higher liability to enter the active side pocket of HER2, L858R, and T790 M, preferable to that of co-crystallized ligands. Modelling simulation was consistent with the acquired biological evaluation.
Keyphrases
- cell cycle
- cell cycle arrest
- cell proliferation
- gene expression
- induced apoptosis
- small cell lung cancer
- cell death
- epidermal growth factor receptor
- endoplasmic reticulum stress
- tyrosine kinase
- oxidative stress
- poor prognosis
- dna methylation
- pi k akt
- binding protein
- high glucose
- single cell
- endothelial cells
- long non coding rna