Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a-e showed higher cytotoxicity than their corresponding Schiff bases 15a-e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC50 in the range of 0.52-6.26 mu M. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC50=0.155-17.08 mu M). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG(1) and G(2)/M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents.