Abstract
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 µM 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.
Published Version
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