Benzene-di-N-octylcarbamates as conformationally constrained phospholipase A(2) inhibitors.
Conformationally constrained 1,2-, 1,3-, and 1,4-benzene-di-N-octylcarbamates are potent reversible competitive inhibitors of Naja mocambique mocambique phospholipase A(2) with the K(i) values of 11, 4, and 15 microM, respectively. With the angle of 120(o) between two C(benzene)-O bonds, 1,3-benzene-di-N-octylcarbamate mimics the preferable eclipsed C(sn-2)-O/C(sn-3)-O conformer of phospholipid in the enzyme-phospholipid complex. Further, a three-step phospholipase A(2) inhibition mechanism by the inhibitor is proposed.
Lin
Gialih
G
Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan. gilin@dragon.nchu.edu.tw
Lin
Yan-Fu
YF
Hwang
Mei-Ting
MT
Lin
Yu-Zen
YZ
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D010179:Pancreas / Q000201:enzymology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010767:Phosphorylcholine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
D002219:Carbamates; D004791:Enzyme Inhibitors; D010743:Phospholipids; D010767:Phosphorylcholine; D010741:Phospholipases A