Selective inhibition of cyclic AMP-dependent protein kinase by amphiphilic triterpenoids and related compounds

Bing Hui Wang, Gideon M. Polya

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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 18α-and 18α-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 μM. These compounds are ineffective or relatively ineffective as inhibitors of various other eukaryote signal-regulated protein kinases namely wheat embryo Ca2+ -dependent protein kinase (CDPK), avian calmodulin-dependent myosin light chain kinase (MLCK) and rat brain Ca2+- 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 (IC50value for cAK 3.0μM). 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 μM, 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 μM, 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.

Original languageEnglish
Pages (from-to)55-63
Number of pages9
JournalPhytochemistry
Volume41
Issue number1
Publication statusPublished - 1 Jan 1996
Externally publishedYes

Keywords

  • Cyclic AMP-dependent protein kinase
  • Protein kinase inhibitors
  • Triterpenoids

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