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

Abstract

A series of new pyrimidine-pyrene hybrids 4, naphtho[1,2-g][1,3,5]oxadiazocine 11 (15), and benzo[5,6]chromeno[4,3-d]pyrimidin-5-one 12 (16) were synthesized via a multicomponent one-pot Biginelli-like synthetic protocol. All the new structures were elucidated using elemental and spectroscopic techniques (¹H- and ¹³C-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 IC₅₀ values were 1.34 μM and 1.90 μM, compared to Erlotinib with an IC₅₀ value of 1.32 μM. Further, compounds 4a and 16 showed substantial cytotoxic effects on HCT-116 cancer cells, with IC₅₀ values of 4.8 and 6.46 μM, respectively. Regarding the EGFR inhibition, compounds 4b and 4c exhibited IC₅₀ values of 77.03 nM and 94.9 nM, respectively, compared to Erlotinib (IC₅₀ = 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.