Synthesis of Polyfluoro Ketones for Selective Inhibition of Human Phospholipase A2 Enzymes

被引:66
作者
Baskakis, Constantinos [2 ]
Magrioti, Victoria [2 ]
Cotton, Naomi [1 ]
Stephens, Daren [1 ]
Constantinou-Kokotou, Violetta [3 ]
Dennis, Edward A. [1 ]
Kokotos, George [2 ]
机构
[1] Univ Calif San Diego, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
[2] Univ Athens, Dept Chem, Organ Chem Lab, Athens 15771, Greece
[3] Agr Univ Athens, Chem Labs, Athens 11855, Greece
关键词
D O I
10.1021/jm800649q
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The development of selective inhibitors for individual PLA(2) enzymes is necessary in order to target PLA(2)-specific signaling pathways, but it is challenging due to the observed promiscuity of known PLA(2) inhibitors. In the current work, we present the development and application of a variety of synthetic routes to produce pentafluoro, tetrafluoro, and trifluoro derivatives of activated carbonyl groups in order to screen for selective inhibitors and characterize the chemical properties that can lead to selective inhibition. Our results demonstrate that the pentafluoroethyl ketone functionality favors selective inhibition of the GVIA iPLA(2), a very important enzyme for which specific, potent, reversible inhibitors are needed. We find that 1,1,1,2,2-pentafluoro-7-phenyl-heptan-3-one (FKGK11) is a selective inhibitor of GVIA iPLA(2) (X-1(50) = 0.0073). Furthermore, we conclude that the introduction of an additional fluorine atom at the alpha' position of a trifluoromethyl ketone constitutes an important strategy for the development of new potent GVIA iPLA(2) inhibitors.
引用
收藏
页码:8027 / 8037
页数:11
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