Inhibition of myosin light chain kinase, cAMP-dependent protein kinase, protein kinase C and of plant Ca(2+)-dependent protein kinase by anthraquinones.
A variety of anthraquinone (anthracene-9,10-dione) derivatives inhibits rat brain Ca(2+)- and phospholipid-activated protein kinase C (PKC) of which the most potent inhibitors are mitoxantrone (1,4-dihydroxy-5,8-bis[2-(hydroxyethylamino)-ethylamino]-9,10- anthracenedione) (IC50 4 microM) and quinalizarin (1,2,5,8-tetrahydroxy-anthraquinone (IC50 4 microM). Anthraquinone derivatives with less polar substitution in positions 1 to 4 and 5 to 8 are less effective as inhibitors of PKC. Wheat germ Ca(2+)-dependent protein kinase (CDPK) assayed with a myosin light chain-based peptide substrate is much less sensitive to inhibition by anthraquinones, the most effective anthraquinone inhibitors being the 1,2,4-trihydroxy (IC50 14 microM), 1,8-dihydroxy-3-methyl (IC50 56 microM) and 1,2,5,8-tetrahydroxy (IC50 65 microM) derivatives. Ca(2+)-calmodulin-dependent myosin light chain kinase (MLCK) is inhibited by a range of di-, tri- and tetrahydroxylated anthraquinones (IC50 values 2 to 53 microM), the most potent inhibitors being the more polar compounds, namely mitoxantrone (IC50 2 microM) and emodin (1,3,8-trihydroxy-6-methylanthraquinone) (IC50 8 microM). Mitoxantrone interacts with calmodulin as determined from abolition of Ca(2+)-dependent fluorescence enhancement of dansyl-calmodulin (IC50 4 microM). A range of anthraquinone derivatives inhibits the catalytic subunit of cAMP-dependent protein kinase (cAK). In a number of cases compounds acting as potent inhibitors of MLCK (such as mitoxantrone and emodin) are very poor inhibitors of cAK and vice versa.
Jinsart
W
W
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
Ternai
B
B
Polya
G M
GM
D000595:Amino Acid Sequence; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001717:Birds; D001921:Brain / Q000201:enzymology; D002417:Cattle; D005895:Gizzard, Avian / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008942:Mitoxantrone / Q000494:pharmacology; D008969:Molecular Sequence Data; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D010940:Plant Proteins / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D051381:Rats; D015290:Second Messenger Systems / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases
D000880:Anthraquinones; D008942:Mitoxantrone; D009219:Myosin-Light-Chain Kinase; D010940:Plant Proteins; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases