The marine natural product curacin A served as the lead compound for the combinatorial synthesis of 6-compound mixture libraries. Fluorous trapping with a vinyl ether tag was used to streamline purification of the heterogeneous multicomponent reaction products and provide chemically clearly defined mixtures. The screening profile of one mixture library, 17mix, was attractive enough to warrant the re-synthesis of the individual compounds, and an evaluation of their biological effects validated the composite data previously obtained on the product mixture. The most active of these compounds inhibited tubulin polymerization with an IC50 of ca. 1 mu M, showed an average growth inhibition activity GI(50) of ca. 250 nM, inhibited [H-3]colchicine binding to tubulin, and blocked mitotic progression at nanomolar concentrations. These compounds represent some of the most patent synthetic curacin A analogues identified to date but have simplified structures, greater water solubility, and increased chemical stability.