Sixteen 2-cyclohexenone and 6-(ethoxycarbonyl)-2-cyclohexenone analogs of combretastatin-A4 (CA-4, 1) were synthesized, and their ability to inhibit the growth of two murine cancer cell lines (B16 melanoma and L1210 leukemia) was determined using an MTT assay. One of the cyclohexenone analogs, 8, which contains the same substituents as CA-4 (1) is the most potent (IC50 = 0.91 μM, L1210). Exposure of A- 10 aortic cells to cyclohexenone 8 and its ester congener 7 produced significant reduction in cellular microtubules, with EC50 values of 27 and 37 μM, respectively. Molecular modeling studies indicate that analog 8 adopts a twisted conformation, similar to CA-4, suggesting that conformation and structure are crucial for activity. These compounds are worthy of further investigation as potential tubulin inhibitors in the quest for novel anti-cancer agents.