Synthesis and evaluation of benzophenone-based photoaffinity labeling analogs of prenyl pyrophosphates containing stable amide linkages

The syntheses of two photoactive prenyl pyrophosphate analogs (1a and 1b) that incorporate stable amide-linked benzophenones are described. Compound 1a contains a single isoprene (C5) unit between the pyrophosphate and benzophenone functionalities while 1b contains a geranyl (C10) moiety. Compounds 1a and 1b are competitive inhibitors of yeast farnesyl protein transferase with respect to farnesyl pyrophosphate and have KI values of 6000 nM and 700 nM. Upon irradiation, [32P]-1b preferentially labels the β-subunits of yeast farnesyl protein transferase and human geranylgeranyl protein transferase.