Preparation, metabolic stability and biological properties of omega-trifluorinated analog of 12-hydroxyeicosatetraenoic acid.

Abstract

12-Hydroxyeicosatetraenoic acid (HETE) is associated with a variety of inflammatory conditions. For studies on pathophysiological function of 12-HETE, metabolically more stable analogs of 12-HETE would be useful. We biologically synthesized 20,20,20-trifluoro-12-HETE (20-F3-12-HETE) by incubating enantioselectively synthesized 20,20,20-trifluoro-arachidonic acid with human platelets. The product was identified by UV absorption spectrophotometry and gas chromatography-mass spectrometry. When 1 microgram 20-F3-12-HETE was incubated with 5 X 10(6) human neutrophils for 45 min, only 5% of the analog was metabolized while 66% of 12-HETE was metabolized in the same incubation condition. With 2 X 10(7) neutrophils, 37% of the analog was metabolized at the same incubation condition while 87% of 12-HETE was metabolized. Thus, by blocking omega-oxidation of 12-HETE with fluorine atoms, the stability of 12-HETE was greatly increased. This result indicates that the omega-oxidation is a major pathway for 12-HETE metabolism. The analog demonstrated as much chemotactic activity on human neutrophils as 12-HETE, and binding affinity of the analog for 12-HETE receptor in human epidermal cell was equal to that of 12-HETE. An analog of 12-HETE, which has extended metabolic stability without alteration of neutrophil chemotactic activity and binding affinity, would be a useful tool for studies on pathophysiological role of 12-HETE in inflammatory conditions.