Selective Inhibition of Eukaryote Protein Kinases by Anti-Inflammatory Triterpenoids

Abstract:

The ursane triterpenoid α-amyrin and the lupane triterpenoid lupeol are potent inhibitors of the catalytic subunit (cAK) of rat liver cyclic AMP-dependent protein kinase (PKA) with IC₅₀ values of 8 and 5 μM, respectively. The palmitate and linoleate esters of α-amyrin and lupeol are also potent inhibitors of cAK (IC₅₀ values in the range of 4-9 μM). α-Amyrin, lupeol and lupeol linoleate are much less potent as inhibitors of rat brain Ca²⁺- and phospholipid-dependent protein kinase (PKC) (IC₅₀ values 32, 82 and 35 μM; respectively) and α-amyrin linoleate and the palmitate esters of lupeol and α-amyrin are ineffective or very poor inhibitors of this protein kinase. These compounds are very poor or ineffective as inhibitors of chicken gizzard calmodulin-dependent myosin light chain kinase (MLCK). α-Amyrin inhibits plant Ca²⁺-dependent protein kinase (CDPK) (IC₅₀ 52 μM) but lupeol and the triterpenoid esters tested are ineffective. α-Amyrin and the linoleate and palmitate esters of α-amyrin and lupeol inhibit cAK in a fashion that is competitive with respect to both peptide substrate and ATP (K_i values in the range 2-6 μM). However, while lupeol is competitive with respect to ATP it is apparently non-competitive with respect to peptide substrate. α-Amyrin also inhibits CDPK competitively and α-amyrin, lupeol and lupeol linoleate are competitive inhibitors of PKC. α-Amyrin and the palmitate esters of lupeol and α-amyrin are competitive inhibitors of the potato high affinity cyclic AMP-binding phosphatase (Pase) but lupeol inhibits the Pase non-competitively. These hydrophobic triterpenoids are further examples of anti-inflammatory triterpenoids that are cAK inhibitors.

Key words:

Protein kinase inhibitors - lupeol - α-amyrin - triterpenoids