Synthesis of Brassilexin Derivatives as Indoleamine-2, 3-Dioxygenase Inhibitors

Posted May 7th, 2010 at 2:53 pm.

Ronke Imbeah-Ampiah

Mentor: Professor Malachowski

One goal of our research group is to synthesize inhibitors of the enzyme indoleamine-2, 3-dioxygenase (IDO). Studies have shown that tumor cells express IDO, which catalyses the cleavage of the amino acid tryptophan. Recently, IDO has also been linked to immunosuppression in cancer.

In addition, brassilexin, a cruciferous phytoalexin, has been reported to be an inhibitor of IDO. A study has shown that brassilexin has antifungal activity and inhibits growth in human cancer cell cultures. This natural compound has also been shown to inhibit IDO noncompetitively. We believe that derivatives of brassilexin will serve as even more potent inhibitors of IDO.

Following a literature precedent, a 4-step synthetic pathway will be used. Readily available oxindole will be converted to indole-2-thione 1. A ß-ketothioamide derivative 2 will be synthesized from the thione via a crossed Claisen condensation reaction. Compound 2 will react with hydroxylamine in the presence of sodium carbonate, ethanol and water to form oxime 3. The oxime will then be converted to a brassilexin derivative 4.

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Peterson et al. Med Chem Res 1993, 473-482

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