Design and synthesis of protein kinase C epsilon selective diacylglycerol lactones (DAG-lactones)

• DAG-lactones with linoleic acid derivatives showed modest selectivity for PKCε.
• DAG-lactones with branched chain showed the best selectivity for PKCε up to 32-fold.
• In nuclear membrane, the selectivity for PKCε versus PKCα was enhanced.

DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the C1 regulatory domain of protein kinase C (PKC). Given the central role of PKC isoforms in cellular signaling, along with their differential biological activities, a critical objective is the design of isoform selective ligands. Here, we report the synthesis of a series of DAG-lactones varying in their side chains, with a particular focus on linoleic acid derivatives. We evaluated their selectivity for PKC epsilon versus PKC alpha both under standard lipid conditions (100% phosphatidylserine, PS) as well as in the presence of a nuclear membrane mimetic lipid mixture (NML). We find that selectivity for PKC epsilon versus PKC alpha tended to be enhanced in the presence of the nuclear membrane mimetic lipid mixture and, for our lead compound, report a selectivity of 32-fold.

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