title: Selective inhibition of cyclic AMP-dependent protein kinase by amphiphilic triterpenoids and related compounds.
abstract: A set of plant- and animal-derived amphiphilic triterpenoids have been shown to be potent and selective inhibitors of the catalytic subunit of rat liver cyclic AMP-dependent protein kinase (cAK). Thus plant-derived 18 alpha- and 18 beta-glycyrrhetinic acid, ursolic acid, oleanolic acid and betulin and animal-derived lithocholic acid, 5-cholenic acid and lithocholic acid methyl ester are inhibitors of cAK with IC50 values (concentrations for 50% inhibition) in the range 4-20 microM. These compounds are ineffective or relatively ineffective as inhibitors of various other eukaryote signal-regulated protein kinases namely wheat embryo Ca(2+)-dependent protein kinase (CDPK), avian calmodulin-dependent myosin light chain kinase (MLCK) and rat brain Ca(2+)- and phospholipid-dependent protein kinase C (PKC). These naturally occurring triterpenoids have a common structural motif involving polar residues located at opposite ends of an otherwise non-polar triterpenoid nucleus. A variety of triterpenoids not possessing this structural motif are relatively inactive as inhibitors of cAK and of CDPK, PKC and MLCK. The terpenoid amphiphilic compound crocetin is also a potent and relatively selective inhibitor of cAK (IC50 value for cAK 3.0 microM). 12-Hydroxystearic acid and 10-hydroxydecanoic acid do not inhibit CDPK, PKC or MLCK but are selective inhibitors of cAK (IC50 values 127 and 138 microM, respectively), consistent with a simple model for amphiphile inhibition of cAK involving two polar groups separated by a non-polar region. However, laurylgallate and 15-pentadecanolide are also potent and selective inhibitors of cAK (IC50 values 1.5 and 20 microM, respectively) although the structures of both of these compounds involve a large non-polar portion associated with only one polar region. Crocetin and the plant-derived amphiphilic triterpenoids described here are the most potent non-aromatic plant-derived inhibitors of cAK yet found.
authors.affiliation: Department of Chemistry, La Trobe University, Budoora, Victoria, Australia.
authors.forename: B H
authors.initials: BH
authors.lastname: Wang
authors.forename: G M
authors.initials: GM
authors.lastname: Polya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D014315:Triterpenes; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases