Phenolic acid phenethylesters and their corresponding ketones: Inhibition of 5-lipoxygenase and stability in human blood and HepaRG cells.

摘要: 5-lipoxygenase (5-LO) catalyzes the biosynthesis of leukotrienes, potent lipid mediators involved in inflammatory diseases, and both 5-LO leukotrienes are validated therapeutic targets. Caffeic acid phenethyl ester (CAPE) is an effective inhibitor leukotriene but susceptible to hydrolysis by esterases. In this study a number CAPE analogues were synthesized with modifications caffeoyl moiety replacement linkage ketone. Several new molecules showed better inhibition than isolated human neutrophils whole blood IC50 values nanomolar (290-520 nmol/L) low micromolar (1.0-2.3 µmol/L) ranges, respectively. Sinapic 2,5-dihydroxy derivatives more stable blood, ketone degraded slowly HepaRG hepatocyte cultures esters. All compounds underwent modification consistent glucuronidation as determined using LC-MS/MS analysis, though modified sinapoyl (10) retained 50% its inhibitory activity after up one hour incubation. This has identified at least analogue, compound 10, that shows favorable properties warrant further vivo investigation antiinflammatory compound.