Asymmetric synthesis of isobenzofuranone derivatives and their unique character as protein kinase Cα (PKCα) activators

Efficient enantio-selective synthesis of conformationally constrained diacylglycerol analogues, 7-substituted isobenzofuranone derivatives, originally developed by us as PKCα ligands, was achieved by asymmetric dihydroxylation and γ-lactone formation via ortho-lithiation and carboxylation. A series of derivatives having straight and/or branched side chains were synthesized and evaluated, and low-nanomolar-concentration affinity ligands and highly potent PKCα activators were found among them. These potent ligands induced phenotypic change of K562 cells, which is characteristic of PKC activators.