S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biochemistry & Molecular Biology (생화학교실) Journal Papers (저널논문_생화학교실)
Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators
- 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
- American Chemical Society
- J Med Chem. 2006 Mar 23;49(6):2028-36.
- 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
- 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).
- 0022-2623 (Print)
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