Inhibition of eukaryote protein kinases and of a cyclic nucleotide-binding phosphatase by prenylated xanthones

Abstract

A series of prenylated xanthones are variously potent inhibitors of the catalytic subunit (cAK) of rat liver cyclic AMP-dependent protein kinase (PKA), rat brain Ca 2+and phospholipid-dependent protein kinase C (PKC), chicken gizzard myosin light chain kinase (MLCK), wheat embryo Ca 2+-dependent protein kinase (CDPK) and potato tuber cyclic nucleotide-binding phosphatase (Pase). The prenylated xanthones examined are mostly derivatives of α-mangostin in which the 3-hydroxyl and 6-hydroxyl are variously substituted with groups R or R′, respectively, or derivatives of 3-isomangostin (mangostanol) in which the 9-hydroxyl is substituted with groups R′ or the prenyl side chain is modified. The most potent inhibitors of cAK have non-protonatable and relatively small R′ and R groups. Conversely, the most potent inhibitors of PKC and MLCK have bulkier and basic R′ groups. Some prenylated xanthones are also potent inhibitors of CDPK. PKC and cAK are competitively inhibited by particular prenylated xanthones whereas the compounds that are the most potent inhibitors of MLCK and CDPK are non-competitive inhibitors. Prenylated xanthones having relatively small and non-protonatable R′ and R groups inhibit a high-affinity cyclic nucleotide binding Pase in a non-competitive fashion.