Anticancer Activities of Tetrasubstituted Imidazole-Pyrimidine-Sulfonamide Hybrids as Inhibitors of EGFR Mutants

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 mu M 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.

Automated summary

A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores were synthesized and evaluated for their anticancer activities. In-vitro screening showed significant growth inhibition of up to 95% against a full 60-cell-line panel at a single dose of 10 μM. The most active compound exhibited in-vitro anticancer activities against abnormal HER2 and two mutants for EGFR. Apoptotic gene expression analysis revealed that lead compounds induced apoptosis in MCF-7 cell line and caused significant changes in the Bax/Bcl-2 expression ratio. One lead compound led to significant cell-cycle S-phase arrest, while another blocked the cell cycle at G1/S-phase causing the accumulation of cells. Docking analysis showed that these two hybrids had higher binding affinity and interaction with the active side pocket of HER2, L858R, and T790 M compared to co-crystallized ligands. Modeling simulation was consistent with the experimental evaluation.