Design, synthesis, and structure–activity relationship of new isobenzofuranone ligands of protein kinase C

Protein kinase C (PKC) is a family of enzymes, which play important roles in intracellular signal transduction. We have designed novel PKC ligands having an isobenzofuranone template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol) with the PKCδ C1B ligand-binding domain. Several isobenzofuranone derivatives were synthesized and their PKCα binding activities were evaluated. The pivaloyl derivative 1f was found to be a strong PKCα ligand, and the structure–activity relationship is well explained by our proposed binding model.