To identify novel therapeutic agents to treatcancer, we synthesized a series of diaryl ether derivatives. Structure–activity relationship studies revealed that thepresence of a chlorine or hydroxyl at the para-position onthe phenyl ring (5h or 5k) significantly enhanced antitumoractivity. Compound 5h had stronger growth inhibitory activityin HepG2, A549, and HT-29 cells than compound 5k,with IC50 values of 2.57, 5.48, and 30.04 lM, respectively. Compound 5h also inhibited the growth of other cells lines,including Hep3B, PLC/PRF5, SMMC-7721, HeLa, andA375, with IC50 values of 2.76, 4.26, 29.66, 18.86, and10.21 lM, respectively. The antitumor activity of compound5h was confirmed by a colony forming assay. Further,our results indicated that the antitumor activity ofcompound 5h may be mediated by enhancing expression ofp21 and cl-caspase3, and leading to apoptosis of cancercells.