Cystic Fibrosis (CF) is a genetic disease that deteriorates the lungs. CF results from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) protein. VX-809 is an FDA-approved CF drug that helps correct the effects of mutations to CFTR. Currently, the binding site of VX-809 to the CFTR protein is unknown. Photoaffinity labels (PALs) are derivatives of drug molecules that can be used to investigate the binding site of a drug with a protein. Reported here is progress toward the synthesis of aryl azide-based PALs derived from VX-809. The synthesis of these PALs follows a convergent synthetic design, with the left-hand side of the molecule synthesized in 53% yield over two steps, and the right-hand side of the molecule synthesized in 76% yield over three steps. These two sides of the molecule are then joined together via an amide coupling reaction in good yields. Three final reactions install an alkyne pull-down tag and form the aryl azide photoaffinity label. The successful synthesis of these PALs will enable investigation of the VX-809 CFTR binding site.

Synthesis of photoaffinity labels derived from VX-809

ACS Fall 2021

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