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 (Ki 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
