title: Molecular pharmacological profile of a novel thiazolinone-based direct and selective 5-lipoxygenase inhibitor.
abstract: OBJECTIVE
  The potency of many 5-lipoxygenase (5-LOX) inhibitors depends on the cellular peroxide tone and the mechanism of 5-LOX enzyme activation. Therefore, new inhibitors that act regardless of the mode of enzyme activation need to be developed. Recently, we identified a novel class of thiazolinone-based compounds as potent 5-LOX inhibitors. Here, we present the molecular pharmacological profile of (Z)-5-(4-methoxybenzylidene)-2-(p-tolyl)-5H-thiazol-4-one, compound C06.
  
  
  METHODS
  Inhibition of 5-LOX product formation was determined in intact cells [polymorphonuclear leukocytes (PMNL), rat basophilic leukaemia-1, RAW264.7] and in cell-free assays [homogenates, 100, 000×g supernatant (S100), partially purified 5-LOX] applying different stimuli for 5-LOX activation. Inhibition of peroxisome proliferator-activated receptor (PPAR), cytosolic phospholipase A(2) (cPLA(2) ), 12-LOX, 15-LOX-1 and 15-LOX-2 as well as cyclooxygenase-2 (COX-2) were measured in vitro.
  
  
  RESULTS
  C06 induced non-cytotoxic, direct 5-LOX inhibition with IC(50) values about 0.66 µM (intact PMNL, PMNL homogenates) and approximately 0.3 µM (cell-free PMNL S100, partially purified 5-LOX). Action of C06 was independent of the stimulus used for 5-LOX activation and cellular redox tone and was selective for 5-LOX compared with other arachidonic acid binding proteins (PPAR, cPLA(2) , 12-LOX, 15-LOX-1, 15-LOX-2, COX-2). Experimental results suggest an allosteric binding distinct from the active site and the C2-like domain of 5-LOX.
  
  
  CONCLUSIONS
  C06 was identified as a potent selective direct 5-LOX inhibitor exhibiting a novel and unique mode of action, different from other established 5-LOX inhibitors. This thiazolinone may possess potential for intervention with inflammatory and allergic diseases and certain types of cancer.
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany. hofmann@pharmchem.uni-frankfurt.de
authors.forename: B
authors.initials: B
authors.lastname: Hofmann
authors.forename: C B
authors.initials: CB
authors.lastname: Rödl
authors.forename: A S
authors.initials: AS
authors.lastname: Kahnt
authors.forename: T J
authors.initials: TJ
authors.lastname: Maier
authors.forename: A A
authors.initials: AA
authors.lastname: Michel
authors.forename: M
authors.initials: M
authors.lastname: Hoffmann
authors.forename: O
authors.initials: O
authors.lastname: Rau
authors.forename: K
authors.initials: K
authors.lastname: Awwad
authors.forename: M
authors.initials: M
authors.lastname: Pellowska
authors.forename: M
authors.initials: M
authors.lastname: Wurglics
authors.forename: M
authors.initials: M
authors.lastname: Wacker
authors.forename: A
authors.initials: A
authors.lastname: Zivković
authors.forename: I
authors.initials: I
authors.lastname: Fleming
authors.forename: M
authors.initials: M
authors.lastname: Schubert-Zsilavecz
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: G
authors.initials: G
authors.lastname: Schneider
authors.forename: D
authors.initials: D
authors.lastname: Steinhilber
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D002474:Cell-Free System; D006801:Humans; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: C000600798:5-(4-methoxybenzylidene)-2-p-tolylthiazol-4(5H)-one; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D001094:Arachidonate 5-Lipoxygenase