Τίτλος:
Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The development of selective inhibitors for individual PLA2 enzymes is necessary in order to target PLA2-specific signaling pathways, but it is challenging due to the observed promiscuity of known PLA2 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 iPLA2, 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 iPLA2 (XI(50) = 0.0073). Furthermore, we conclude that the introduction of an additional fluorine atom at the α′ position of a trifluoromethyl ketone constitutes an important strategy for the development of new potent GVIA iPLA2 inhibitors. © 2008 American Chemical Society.
Συγγραφείς:
Baskakis, C.
Magrioti, V.
Cotton, N.
Stephens, D.
Constantinou-Kokotou, V.
Dennis, E.A.
Kokotos, G.
Περιοδικό:
Journal of Medicinal Chemistry
Λέξεις-κλειδιά:
1,1,1,2,2 pentafluoro 7 phenylheptan 3 one; carbonyl derivative; cytosolic phospholipase A2; fkgk 11; fluorine derivative; ketone derivative; pentafluoroketone derivative; phospholipase A2 inhibitor; tetrafluoroketone derivative; trifluoroketone derivative; unclassified drug, article; concentration response; drug design; drug potency; drug structure; drug synthesis; enzyme inhibition; enzyme specificity; fluorine nuclear magnetic resonance; nonhuman; signal transduction, Carbon; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Humans; Ketones; Magnetic Resonance Spectroscopy; Micelles; Models, Chemical; Phospholipases A2, Cytosolic; Phospholipids; Signal Transduction; Substrate Specificity
