Publications
Detailed Information
Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators
Cited 8 time in
Web of Science
Cited 9 time in Scopus
- Authors
- Issue Date
- 2006-03-17
- Publisher
- American Chemical Society
- Citation
- J Med Chem. 2006 Mar 23;49(6):2028-36.
- Keywords
- Amyloid Precursor Protein Secretases ; Animals ; Aspartic Endopeptidases ; Cell Line, Tumor ; Diglycerides/*chemical synthesis/chemistry/pharmacology ; Endopeptidases/*metabolism ; Enzyme Activators/*chemical synthesis/chemistry/pharmacology ; Humans ; Lactones/*chemical synthesis/chemistry/pharmacology ; Ligands ; Phorbol 12,13-Dibutyrate/metabolism/pharmacology ; Protein Binding ; Protein Kinase C-alpha/*metabolism ; Rats ; Stereoisomerism ; Structure-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
https://hdl.handle.net/10371/28216
- Files in This Item:
- There are no files associated with this item.
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.