Twenty-one α,β-unsaturated ketone analogs of combretastatin-A4 (CA-4) that were designed for good solubility in aqueous media were synthesized. Compounds defined as Type A were derived from phenylacetone, in which subclass I contained ortho-, meta- or no substituents, sub-class II contained para-substituents, and sub-class III consisted of two substituents. Type B compounds were derived from cyclopropyl 2-fluorobenzyl ketone. The cis-configuration of the target compounds was ascertained through a single crystal X-ray crystallographic analysis of the fluorine-containing compound 8f. Five of the analogs, 8c, 8j and 8l of Type A and 9d and 9i of Type B, were shown to display modest cytotoxic potency (IC50 in the 3.8 – 21 μM range) against the growth of murine melanoma (B16) and leukemia (L1210) cells in culture. Compounds 8j, 8l and 9i were further tested against MDA-MB-435 human melanoma cells. The cyclopropanecontaining compound 9i was the most potent; with an IC50 value of 2.4 μM. Even though no appreciable effects on interphase microtubules were observed when A-10 cells were treated with 30 μM 8j or 8l, compound 9i caused extensive microtubule depolymerization at this concentration. These results suggest that compound 9i of Type B has a similar mechanism of action as CA-4 whilst compounds 8j and 8l of Type B are likely to have a different mechanism of action.