New derivatives based on zerumbone scaffold as anticancer inhibitors: Synthesis, in vitro anticancer evaluation, docking, and MD simulation studies

A three-step procedure was applied to synthesize seven novel zerumbone ethers 7a-g with N-(4-hydroxybenzyl) benzamide, N-(4-hydroxybenzyl) substituted benzamide, and N-(4-hydroxybenzyl) cinnamamide moieties, including simultaneous O- and N-acylations, ester hydrolysis, and O-alkylation. The structure of intermediates and target compounds was elucidated using one-dimensional and two-dimensional nuclear magnetic resonance, and high-resolution mass spectrometry data. Their cytotoxic activities were screened on three human cancer cell lines HepG2, LU-1, and HeLa. The results showed that ethers 7a-g exhibited activity against all tested cell lines with IC50 values ranging from 1.71 to 6.86 mu M and stronger than zerumbone, approximately 10-35 folds. Theoretically, the mode of their anticancer action was studied based on predicting the ability to inhibit Fibroblast Growth Factor Receptor 1 and Vascular Endothelial Growth Factor Receptor 2 proteins using docking and molecular dynamic simulation studies. The interaction of 7a-g with important amino acids in the active binding sites of protein Fibroblast Growth Factor Receptor 1 and Vascular Endothelial Growth Factor Receptor 2, and Umbrella Effect formation explained the significant improvement in their cytotoxic activities compared to the parent compound zerumbone.