Design, Synthesis, and Characterization of Novel sn -1 Heterocyclic DAG-Lactones as PKC Activators
Year: 2021
Type: article
Abstract: 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 PKCα and PKCε with nanomolar affinity. Remarkably, 10B12 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.
Source: Journal of Medicinal Chemistry
Institutions: Consejo Nacional de Investigaciones Científicas y Técnicas, National Institute of Industrial Technology, Jefferson Einstein Philadelphia Hospital, University of Pennsylvania, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Frederick National Laboratory for Cancer Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, Frederick National Laboratory for Cancer Research, Consejo Nacional de Investigaciones Científicas y Técnicas, National Institutes of Health, Agencia Nacional de Promoción Científica y Tecnológica, National Cancer Institute, National Institute of Environmental Health Sciences, Fondo para la Investigación Científica y Tecnológica
Awards: G1497287268, G1845495836, CXCL13: a mediator of prostate cancer progression, Protein kinase C and lung carcinogenesis, G3503792436, G380550198, G386607036, G4585269469, Protein kinase C and lung carcinogenesis, G4988656331, G5298623163, G5344391199, G6412070859, G7378882120, G9000022176, G9000092662, G9000126031
OpenAlex ID: W3186592205