Design, synthesis, characterization, computational analysis, structure-activity relationship, and investigation of the anticancer potential of novel dibromodibenzoazepine-based hybrid structures

In this study, ten novel dibromodibenzoazepine-substituted triazole hybrid compounds (AZ1-AZ10) were designed via a molecular hybridization approach and synthesized using click chemistry methodology. In the synthesis, the dibromodibenzoazepine derivative (12) was initially synthesized via bromination. Subsequent propargylation yielded the key intermediate, dibromodibenzoazepine-propargyl derivative (13). The Cu (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of propargyl derivative (13) with various substituted azide derivatives afforded the target hybrid compounds in high yields. The structures of these compounds were characterized using various spectroscopic techniques, including H-1 NMR, C-13 NMR, and MS. Among the synthesized compounds, AZ9 was determined to have the highest cytotoxicity on breast and colon cancer cell lines, including BT20, MCF7, MDA-MB-231, and HT29 with the IC50 values of 0.54 +/- 0.09 mu M, 1.83 +/- 0.87 mu M, 3.88 +/- 0.15 mu M, and 5.31 +/- 0.38 mu M, respectively. In addition, AZ8 showed the cytotoxicity on BT20 and HT29 cells below 10 mu M. The cytotoxicity of AZ10 in studied cancer cell lines was calculated below 20 mu M. The compounds were investigated by computational analysis including molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics with Generalized Born and Surface Area Solvation (MM/GBSA), and ADME predictions. As a result, AZ8-AZ10 may be promising anticancer agents targeting SphK1 and CDK6 to provide new perspectives for the design and development of novel click products.