Design, Synthesis and Characterization of Novel sn-1 Heterocyclic DAGlactones as PKCe Activators
Year: 2020
Type: preprint
Abstract: In this study we describe the synthesis and characterization of novel diacylglycerol (DAG)-lactones that bind to protein kinase C (PKC). DAG-lactones proved to be useful templates for the design of potent and selective C1 domain ligands. The ester moiety at sn-1 position, a common feature in this template, is relevant for interaction with the PKC C1 domains, although it represents a labile group susceptible to endogenous esterases. Our studies identified the DAG-lactone 10B12 with an isozazole ring as a nanomolar affinity PKC ligand. This compound shows preferential selectivity for PKCepsilon, and strongly activates actin cytoskeleton reorganization into peripheral ruffles in cancer cells, an effect mediated by PKCepsilon. Therefore, introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC selectivity.
Source: ChemRxiv
Institutions: Consejo Nacional de Investigaciones Científicas y Técnicas, National Institute of Industrial Technology, National Institutes of Health, Jefferson Einstein Philadelphia Hospital, National Cancer Institute, Center for Cancer Research, University of Pennsylvania, Frederick National Laboratory for Cancer Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4233569854