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Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, Jeewoo | - |
dc.contributor.author | Kang, Ji-Hye | - |
dc.contributor.author | Han, Kee-Chung | - |
dc.contributor.author | Kim, Yerim | - |
dc.contributor.author | Kim, Su Yeon | - |
dc.contributor.author | Youn, Hae-Suk | - |
dc.contributor.author | Mook-Jung, Inhee | - |
dc.contributor.author | Kim, Hee | - |
dc.contributor.author | Han, Jee Hye Lo | - |
dc.contributor.author | Ha, Hee Jin | - |
dc.contributor.author | Kim, Young Ho | - |
dc.contributor.author | Marquez, Victor E. | - |
dc.contributor.author | Lewin, Nancy E. | - |
dc.contributor.author | Pearce, Larry V. | - |
dc.contributor.author | Lundberg, Daniel J. | - |
dc.contributor.author | Blumberg, Peter M. | - |
dc.date.accessioned | 2010-01-07T05:06:33Z | - |
dc.date.available | 2010-01-07T05:06:33Z | - |
dc.date.issued | 2006-03-17 | - |
dc.identifier.citation | J Med Chem. 2006 Mar 23;49(6):2028-36. | en |
dc.identifier.issn | 0022-2623 (Print) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16539391 | - |
dc.identifier.uri | https://hdl.handle.net/10371/28216 | - |
dc.description.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). | en |
dc.language.iso | en | en |
dc.publisher | American Chemical Society | en |
dc.subject | Amyloid Precursor Protein Secretases | en |
dc.subject | Animals | en |
dc.subject | Aspartic Endopeptidases | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | Diglycerides/*chemical synthesis/chemistry/pharmacology | en |
dc.subject | Endopeptidases/*metabolism | en |
dc.subject | Enzyme Activators/*chemical synthesis/chemistry/pharmacology | en |
dc.subject | Humans | en |
dc.subject | Lactones/*chemical synthesis/chemistry/pharmacology | en |
dc.subject | Ligands | en |
dc.subject | Phorbol 12,13-Dibutyrate/metabolism/pharmacology | en |
dc.subject | Protein Binding | en |
dc.subject | Protein Kinase C-alpha/*metabolism | en |
dc.subject | Rats | en |
dc.subject | Stereoisomerism | en |
dc.subject | Structure-Activity Relationship | en |
dc.title | Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators | en |
dc.type | Article | en |
dc.contributor.AlternativeAuthor | 이지우 | - |
dc.contributor.AlternativeAuthor | 강지혜 | - |
dc.contributor.AlternativeAuthor | 한기정 | - |
dc.contributor.AlternativeAuthor | 김예림 | - |
dc.contributor.AlternativeAuthor | 김수연 | - |
dc.contributor.AlternativeAuthor | 윤혜숙 | - |
dc.contributor.AlternativeAuthor | 묵인희 | - |
dc.contributor.AlternativeAuthor | 김희 | - |
dc.contributor.AlternativeAuthor | 하희진 | - |
dc.contributor.AlternativeAuthor | 김영호 | - |
dc.identifier.doi | 10.1021/jm0509391 | - |
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