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Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators

Cited 7 time in Web of Science Cited 8 time in Scopus
Authors
Lee, Jeewoo; Kang, Ji-Hye; Han, Kee-Chung; Kim, Yerim; Kim, Su Yeon; Youn, Hae-Suk; Mook-Jung, Inhee; Kim, Hee; Han, Jee Hye Lo; Ha, Hee Jin; Kim, Young Ho; Marquez, Victor E.; Lewin, Nancy E.; Pearce, Larry V.; Lundberg, Daniel J.; Blumberg, Peter M.
Issue Date
2006-03-17
Publisher
American Chemical Society
Citation
J Med Chem. 2006 Mar 23;49(6):2028-36.
Keywords
Amyloid Precursor Protein SecretasesAnimalsAspartic EndopeptidasesCell Line, TumorDiglycerides/*chemical synthesis/chemistry/pharmacologyEndopeptidases/*metabolismEnzyme Activators/*chemical synthesis/chemistry/pharmacologyHumansLactones/*chemical synthesis/chemistry/pharmacologyLigandsPhorbol 12,13-Dibutyrate/metabolism/pharmacologyProtein BindingProtein Kinase C-alpha/*metabolismRatsStereoisomerismStructure-Activity Relationship
Abstract
Using as our lead structure a potent PKC ligand (1) that we had previously described, we investigated a series of branched DAG-lactones to optimize the scaffold for PKC binding affinity and reduced lipophilicity, and we examined the potential utility of select compounds as alpha-secretase activators. Activation of alpha-secretase upon PKC stimulation by ligands causes increased degradation of the amyloid precursor protein (APP), resulting in enhanced secretion of sAPPalpha and reduced deposition of beta-amyloid peptide (Abeta), which is implicated in the pathogenesis of Alzheimer's disease. We modified in a systematic manner the C5-acyl group, the 3-alkylidene, and the lactone ring in 1 and established structure-activity relationships for this series of potent PKC ligands. Select DAG-lactones with high binding affinities for PKC were evaluated for their abilities to lead to increased sAPPalpha secretion as a result of alpha-secretase activation. The DAG-lactones potently induced alpha-secretase activation, and their potencies correlated with the corresponding PKC binding affinities and lipophilicities. Further investigation indicated that 2 exhibited a modestly higher level of sAPPalpha secretion than did phorbol 12,13-dibutyrate (PDBu).
ISSN
0022-2623 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16539391

http://hdl.handle.net/10371/28216
DOI
https://doi.org/10.1021/jm0509391
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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