Abstract

Combretastatin A-4, isolated from the South African bush willow, is well known to bind readily to β-tubulin and disrupt vascular function. Chalcones with structural features similar to Combretastatin A-4 is also known to inhibit tubulin by disrupting its formation or functionality. Several heterocyclic chalcone derivatives have been synthesized in the literature and act as tubulin binding agents. This research examines the synthesis of indole chalcone analogs of Combretastatin A-4 and α-halo substituted indole chalcones utilizing the Hemetsberger-Knittel indole methodology. In the first step, an aldol condensation produced a vinyl azide from a benzaldehyde and ethyl azidoacetate. The product was thermolyzed to produce an indole ester. The indole ester is then reduced with lithium aluminum hydride and subsequently oxidized with IBX to form the indole aldehyde. The indole aldehyde was combined with a substituted acetophenone in a condensation reaction to form the indole chalcone. The structural features of the indole aldehyde are important when reacting with the acetophenones, molecules with ketone functionality. The synthesis of the α-halo indole chalcones utilize the same condensation reaction with the indole aldehyde and an α-halo 3,4,5-trimethoxy acetophenone. The α-halo acetophenone analogs were made through two successive substitutions. All of the reactions produced pure product in 60-80% yield except the final condensation reaction. The indole chalcone synthesis is still causing problems and new synthetic schemes are being explored.

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