Design, Synthesis, and Characterization of Novel sn-1 Heterocyclic DAG-Lactones as PKC Activators

DAG-lactones represent useful templates for the design of potent and selective C1 domain ligands for PKC isozymes. The ester moiety at the sn-1 position, a common feature in this template, is relevant for C1 domain interactions, but it represents a labile group susceptible to endogenous esterases. An interesting challenge involves replacing the ester group of these ligands while still maintaining biological activity. Here, we present the synthesis and functional characterization of novel diacylglycerol-lactones containing heterocyclic ring substituents at the sn-1 position. Our results showed that the new compound 10B12, a DAG-lactone with an isoxazole ring, binds PKCa and PKC epsilon with nanomolar affinity. Remarkably, 10B12 displays preferential selectivity for PKC epsilon translocation in cells and induces a PKC epsilon-dependent reorganization of the actin cytoskeleton into peripheral ruffles in lung cancer cells. We conclude that introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC isozyme selectivity.

Automated summary

DAG-lactones are useful templates for designing potent and selective ligands for PKC isozymes, with the ester moiety at the sn-1 position playing a critical role in C1 domain interactions. By introducing a stable isoxazole ring as an ester surrogate in DAG-lactones, it is possible to achieve selectivity for PKC isozymes.