Synthesis of some new pyrimidine-based pyrene/benzochromene hybrids as EGFR kinase inhibitors in HCT-116 cancer cells through apoptosis.

A series of new pyrimidine-pyrene hybrids 4, naphtho[1,2-][1,3,5]oxadiazocine 11 (15), and benzo[5,6]chromeno[4,3-]pyrimidin-5-one 12 (16) were synthesized a multicomponent one-pot Biginelli-like synthetic protocol. All the new structures were elucidated using elemental and spectroscopic techniques (H- and C-NMR, HRMS, MALDI-TOF, IR). The cytotoxicity of the new compounds was evaluated against "HCT-116, HepG2, and WI-38" cell lines. Compounds 4b and 4c demonstrated the best inhibitory potency against HCT-116 cancer cells, where their IC values were 1.34 μM and 1.90 μM, compared to Erlotinib with an IC value of 1.32 μM. Further, compounds 4a and 16 showed substantial cytotoxic effects on HCT-116 cancer cells, with IC values of 4.8 and 6.46 μM, respectively. Regarding the EGFR inhibition, compounds 4b and 4c exhibited IC values of 77.03 nM and 94.9 nM, respectively, compared to Erlotinib (IC = 72.3 nM). Compound 4b treatment induced apoptosis in HCT-116 cancer cells by 30.2-fold, arresting the cell cycle at the G1-phase. It upregulated the apoptosis-related genes using the RT-PCR. Finally, a molecular docking study highlighted the binding interactions with key amino acids inside the EGFR binding site.