Design, Synthesis, and Characterization of Novel <i>sn</i>-1 Heterocyclic DAG-Lactones as PKC Activators.
Elhalem E, Bellomo A, Cooke M, Scravaglieri A, Pearce LV, Peach ML, Gandolfi Donadío L, Kazanietz MG, Comin MJ.
DAG-lactones represent useful templates for the design of potent and selective C1 domain ligands for PKC isozymes. The ester moiety at the <i>sn</i>-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 <i>sn</i>-1 position. Our results showed that the new compound <b>10B12</b>, a DAG-lactone with an isoxazole ring, binds PKCα and PKCε with nanomolar affinity. Remarkably, <b>10B12</b> displays preferential selectivity for PKCε translocation in cells and induces a PKCε-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.