期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 90, 期 -, 页码 332-341出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.11.025
关键词
Protein kinase C; Diacylglycerol lactone; PKC-epsilon
资金
- National Research Foundation of Korea [R11-2007-107-02001-0]
- Intramural Research Program of the National Institutes of Health, Center for Cancer Research, NCI [Z1A BC 005270]
- National Research Foundation of Korea [R11-2007-107-02001-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
DAG-lactones afford a synthetically accessible, high affinity platform for probing structure activity relationships at the Cl 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. (C) 2014 Elsevier Masson SAS. All rights reserved.
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