Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFR(WT), EGFR(T790M), and EGFR(L858R))

Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for 10c. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFR(WT), EGFR(T790M), and EGFR(L858R) where compound 10d was the best inhibitor with IC50 = 0.097, 0.280, and 0.051 & mu;M, respectively, compared to erlotinib (IC50 = 0.082 & mu;M, 0.342 & mu;M, and 0.055 & mu;M, respectively). Safety profile was validated using normal human lung (IMR-90) cells. 10c and 10d disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs.

Automated summary

The Hexahydroquinoline (HHQ) scaffold was utilized to develop a new series of anticancer agents. Thirty-two new compounds were synthesized and enantiomerism was confirmed through X-ray crystallography. Thirteen compounds exhibited moderate to good activity against NCI 60 cancer cell lines, with compound 10c showing the highest activity. In comparison to the reference drug erlotinib, compound 10d demonstrated superior inhibitory activity against EGFR(WT), EGFR(T790M), and EGFR(L858R), with IC50 values of 0.097, 0.280, and 0.051 & mu;M, respectively. Safety profiling using normal human lung cells validated the safety of compounds 10c and 10d. Molecular docking analysis provided insights into the potential binding interactions and affinities of the compounds in the active sites of the three versions of EGFR.