Parthenolide and helenalin are two sesquiterpene lactone natural products that contain an exocyclic methylene butyrolactone, and have a variety of biological activities including anti-proliferative effects. Multiple molecular targets have been suggested to interact with both compounds. Our lab and others have demonstrated that the exocyclic methylene butyrolactone pharmacophore is necessary for this activity, and reacts with cysteines within a cell proteome forming a covalent linkage between the target protein and the molecule via a Michael addition. Our work takes advantage of this covalent linkage to develop small molecule probes containing alkyne tethers for the attachment of biotin and fluorescent moieties. This approach facilitates the enrichment and identification of target proteins to establish mechanisms of biological activity. The utilities of these probes for studies in human cancer cells will be presented.

Natural product inspired alkyne probes with cysteine reactive exocyclic methylene butyrolactones

248th National Meeting (2014)

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