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Abstract A set of plant- and animal-derived amphiphilic triterpenoids have been shown to be potent and selective Biophys inhibitors of the catalytic subunit of rat liver cyclic AMP-dependent protein kinase (CAK). Thus plant-derived 18x Maheshwar acid and lithocholic acid methyl ester are inhibitors of CAK with IC50 values (concentrations for 50% inhibition) in and 18ẞ-glycyrrhetinic acid, ursolic acid, oleanolic acid and betulin and animal-derived lithocholic acid, 5-cholenic the range 4-20 μM. These compounds are ineffective or relatively ineffective as inhibitors of various other eukaryote Maheshwar 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 wton, R. P 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 (ICsovalue for CAK 3.0 μM). 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.

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