Design, click-based synthesis, molecular docking, molecular dynamics and anticancer activity of new...

The application of simulated research approaches for the discovery and development of novel compounds as promising cancer drug candidates have still garnered widespread attention as an important goal in medicinal chemistry. In such context, a novel derived series of modified glycosides based on an isoindole-1,2,3-triazole-1,4-disubstituted-aryl hybrid system were synthesized from the terminal acetylenic compound (prepared from propargylation of 2-(4-hydroxyphenyl)isoindoline-1,3-dione (1)) and different glycosyl azides via click-based strategy. Furthermore, the afforded acetylated Iso-idolinedione-N¹-glycosyl-1,2,3-triazole products were diacetylated to give the derived glycosyl-triazoles with deacetylated hydroxyls. On the other hand, the C-glycosyl analogues were also prepared from the (azidoethoxy)phenyl)isoindoline-1,3-dione followed by deprotection process. The cytotoxicity behaviour of resulted isoindoline-dione based 1,2,3-triazole glycosides was investigated towards the human cancer cells: human breast (PC3), colorectal (HCT-116), and hepatic (HepG-2) lines. The influence of attachment of the sugar part on the cytotoxicity results was obvious and the type of the attached sugar moiety where the glycosyl-1,2,3-triazoles with the xylopyranosyl moiety (compounds 6, 9 and 16) and galactopyranosyl (compound 8) were the most active. The latter accounted for the specific effect of the type of the sugar moiety. Docking investigation into epidermal growth factor receptor (EGFR) indicated potential interacting binding behaviours and mechanisms of inhibition. Molecular dynamics investigation revealed the possibility of attaining a stable binding mode of the glycoside 8 into EGFR's site as well as the structural integrity of the catalytic domain. The electronic structure, molecular orbitals, and electrostatic potential of compound 8 were analysed by Density functional theory (DFT) calculations. HOMO-LUMO analysis demonstrated the electron-donating and electron-accepting potency, supporting the anticancer potential and aligning with the docking and dynamics results.