Abstract

Drugs that inhibit tubulin polymerization have largely been focused on in the field of cancer research. Combretastatin A-4 (CA-4) binds to the colchicine site of β-tubulin, thus inhibiting tubulin polymerization and inducing eventual tumoral vasculature shutdown. Structural modifications of CA-4 have been researched in order to overcome the solubility and stereochemical barriers the drug poses in its original form. Analogs bearing indole and chalcone moiety have shown increased drug efficacy when these structural modifications are implemented in CA-4 compounds. The focus of this project is to synthesize a CA-4 analog containing an indole derivative and a chalcone core. A halogen is incorporated alpha to the carbonyl within the chalcone core of the CA-4 derivative. Synthesis of the substituted indole aldehyde utilizes Hemetsberger-Knittel methodology. The chalcone of interest is formed in the final step through an aldol condensation reaction between a halogenated acetophenone and the indole derivative. A few steps of the indole synthesis were accomplished, but the desired indole aldehyde was ultimately unable to be obtained. The brominated acetophenone was synthesized in several trials and purified via column chromatography. A fluorination reaction involving the purified brominated acetophenone likely yielded the desired fluorinated acetophenone, based on the spectral data acquired after implementing multiple compound identification techniques. Because the indole synthesis prevented the overall synthetic scheme from moving forward, a commercially available indole aldehyde was reacted with brominated acetophenone to form an α-halo indole-chalcone. Further spectral analysis of the product from this aldol condensation reaction is needed to determine if the expected chalcone product was produced. Future research for this project involves synthesizing halogenated indole-chalcones, in which commercially available indoles will be reacted with halogenated acetophenones in order to determine optimal reaction conditions for obtaining the desired chalcone products.

How to Cite