Protein kinase C translocation by modified phorbol esters with functionalized lipophilic regions
| Autor: | Daniel F. Harvey, Jennifer Giorgione, Thomas M. Bertolini, Alexandra C. Newton |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Stereochemistry
Croton Oil Carboxylic acid Croton tiglium Carboxylic Acids Ligands chemistry.chemical_compound Membrane Lipids Structure-Activity Relationship Amide Phorbol Esters Croton oil Enzyme Inhibitors Protein kinase C Protein Kinase C chemistry.chemical_classification biology Molecular Structure Vesicle Organic Chemistry biology.organism_classification Enzyme Activation Kinetics chemistry Biochemistry Enzyme inhibitor Phorbol biology.protein Diterpenes |
| Zdroj: | The Journal of organic chemistry. 68(13) |
| ISSN: | 0022-3263 |
| Popis: | Several novel phorbol esters were prepared with polar functional groups terminating their C12 and/or C13 acyl chains. Designed to be inhibitory protein kinase C (PKC) ligands, these phorbol analogues contain various polar functional groups (amide, ester, carboxylic acid, or quaternary ammonium salt) to prevent membrane insertion of the PKC-phorbol ester complex. All phorbol derivatives were synthesized with use of diterpene starting materials obtained from croton oil, the seed oil of Croton tiglium. The ability of these derivatives to recruit PKC to the lipid bilayer-a usual requirement for enzyme activation-was determined by using a sucrose-loaded vesicle assay. Phorbol 12-octanoate-13-acetate derivatives translocate PKC-betaII to increasing degrees as the functionality on the C12 ester becomes more hydrophobic. Likewise, PKC translocation by carboxylic acid-containing phorbol esters was dependent upon length and saturation of the hydrocarbon tether. The most promising PKC inhibitors had short carboxylic acids capping their C12 and C13 acyl chains, since these compounds did not recruit PKC to any appreciable extent. |
| Databáze: | OpenAIRE |
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