Synthesis and biological evaluation of a focused mixture library of analogues of the antimitotic marine natural product curacin A

The marine natural product curacin A served as the lead compound for the co mbinatorial synthesis of 6-compound mixture libraries. Fluorous trapping wi th a vinyl ether tag was used to streamline purification of the heterogeneo us multicomponent reaction products and provide chemically clearly defined mixtures. The screening profile of one mixture library, 17mix, was attracti ve enough to warrant the re-synthesis of the individual compounds, and an e valuation of their biological effects validated the composite data previous ly obtained on the product mixture. The most active of these compounds inhi bited 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 concentrat ions. 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.