Wang B H, Ternai B, Polya G M
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
Biol Chem Hoppe Seyler. 1994 Aug;375(8):527-35. doi: 10.1515/bchm3.1994.375.8.527.
The phenanthrenemethanol antimalarial halofantrine is a potent inhibitor of bovine heart and rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK) (IC50 values 2.1 microM and 0.6 microM, respectively). The inhibition of rat liver cAK by halofantrine is non-competitive with respect to both ATP and to the synthetic peptide substrate employed (LRRASLG). Halofantrine is a poor inhibitor of calmodulin-dependent myosin light chain kinase (MLCK) and wheat embryo Ca(2+)-dependent protein kinase (CDPK) and does not inhibit rat brain Ca(2+)- and phospholipid-dependent protein kinase C (PKC). In contrast, the acridine-based antimalarial quinacrine and a variety of quinoline-based antimalarials are very poor inhibitors of cAK, the best inhibitor being chloroquine (IC50 for bovine heart cAK, 80 microM). Quinacrine and the quinoline-based antimalarials variously inhibit CDPK, PKC and MLCK albeit at relatively high concentrations (about 1 to 4 x 10(-4) M), the best inhibitors found being primaquine, pentaquine and mefloquine (IC50 values for MLCK 49, 103 and 33 microM, respectively). A number of phenanthrene derivatives having a 9-hydroxy or 9-keto substituent, namely phenanthrenequinone, 6(5H)-phenanthridinone and 9-phenanthrol are potent inhibitors of bovine heart cAK (IC50 values 8, 10 and 10 microM, respectively) and of MLCK (IC50 values 6, 53 and 10 microM, respectively). The selective, high affinity interaction of halofantrine with cAK may contribute to biological effects in vivo of this clinically-employed antimalarial compound.
菲并甲醇抗疟药卤泛群是牛心脏和大鼠肝脏环磷酸腺苷依赖性蛋白激酶催化亚基（cAK）的强效抑制剂（IC50值分别为2.1 microM和0.6 microM）。卤泛群对大鼠肝脏cAK的抑制作用对于ATP和所使用的合成肽底物（LRRASLG）而言均为非竞争性。卤泛群是钙调蛋白依赖性肌球蛋白轻链激酶（MLCK）和小麦胚钙依赖性蛋白激酶（CDPK）的弱抑制剂，并且不抑制大鼠脑钙和磷脂依赖性蛋白激酶C（PKC）。相比之下，基于吖啶的抗疟药喹吖因和多种基于喹啉的抗疟药是cAK的非常弱的抑制剂，最佳抑制剂是氯喹（对牛心脏cAK的IC50，80 microM）。喹吖因和基于喹啉的抗疟药尽管在相对高的浓度（约1至4×10^(-4) M）下对CDPK、PKC和MLCK有不同程度的抑制作用，所发现的最佳抑制剂是伯氨喹、戊喹和甲氟喹（对MLCK的IC50值分别为49、103和33 microM）。一些具有9-羟基或9-酮取代基的菲衍生物，即菲醌、6(5H)-菲啶酮和9-菲醇是牛心脏cAK（IC50值分别为8、10和10 microM）和MLCK（IC50值分别为6、53和10 microM）的强效抑制剂。卤泛群与cAK的选择性高亲和力相互作用可能有助于这种临床使用的抗疟化合物在体内的生物学效应。
