Design, synthesis, and structure-activity relationship studies of novel diaryl ether amides as potential antitumor agents

Sorafenib is a drug that has been verified to be effective on hepatoma cells. Three series of diaryl ethers have been designed and synthesized based on the structure of sorafenib. The 5m compound shows better inhibitory potency against HepG2 cells (IC50 = 1.96 mu M) than sorafenib (IC50 = 9.61 mu M). These results have been verified with MTT assay and colony-forming assay. Moreover, compound 5m exhibits good antitumor activities against PLC/PRF5, HeLa, A549, and HT-29 cell lines. The excellent bioactivity of compound 5m confirms that a single optical conformation is superior to the racemate. A western blotting analysis indicates that compound 5m induces the apoptosis of HepG2 cells by enhancing the protein levels of p21 and Cl-caspase3.