A simplified bicyclic scaffold inspired by the antifungal natural product sordarin was designed and synthesized which maintains the carboxylic acid/aldehyde (or nitrile) pharmacophore. Docking studies with the target for sordarin, the fungal protein eukaryotic elongation factor 2 (eEF2), suggested that the novel scaffolds may bind productively. A densely functionalized chiral cyclopentadiene was constructed in 8 steps and utilized in a Diels-Alder reaction with acrylonitrile. The resulting [2.2.1] cycloheptene was transformed into a scaffold possessing vicinal carboxylic acid and nitrile groups, with orientations predicted to provide high affinity for eEF2. The synthetic approach disclosed here sets the stage for a renewed medicinal chemistry campaign against eEF2.
Wu, Yibiao and Dockendorff, Chris, "Synthesis of a Novel Bicyclic Scaffold Inspired by the Antifungal Natural Product Sordarin" (2018). Chemistry Faculty Research and Publications. 963.
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