A series of all-trans-1-aryl-4-aryl-5-aryl-2,4-pentanediene-1-one (3), a hybridized form of chalcone and combretastatin, was synthesized and evaluated against a panel of cancer cell lines, including B16, murine melanoma; HCT116, colon cancer; A431, human epidermoid carcinoma; and human umbilical venous endothelial cells (HUVEC). Structure-activity relationships analysis of this series revealed that a 2,5-dihydroxyphenyl at position 1 of the 2,4-pentanediene-1-one was essential for cytotoxicity. all-trans-1-(2,5-Dihydroxyphenyl)-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,4-pentanediene-1-one (3a) was the most potent compound from this series.