Open AccessPhenolic acid phenethylesters and their corresponding ketones: Inhibition of 5‐lipoxygenase and stability in human blood and HepaRG cells
Author(s) -
Mbarik Maroua,
Poirier Samuel J.,
Doiron Jérémie,
Selka Ayyoub,
Barnett David A.,
Cormier Marc,
Touaibia Mohamed,
Surette Marc E.
Publication year - 2019
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.524
Subject(s) - lipoxygenase , arachidonate 5 lipoxygenase , chemistry , human blood , pharmacology , biochemistry , chromatography , medicine , enzyme , physiology , arachidonic acid
Abstract 5‐lipoxygenase (5‐LO) catalyzes the biosynthesis of leukotrienes, potent lipid mediators involved in inflammatory diseases, and both 5‐LO and the leukotrienes are validated therapeutic targets. Caffeic acid phenethyl ester (CAPE) is an effective inhibitor of 5‐LO and leukotriene biosynthesis but is susceptible to hydrolysis by esterases. In this study a number of CAPE analogues were synthesized with modifications to the caffeoyl moiety and the replacement of the ester linkage with a ketone. Several new molecules showed better inhibition of leukotriene biosynthesis than CAPE in isolated human neutrophils and in whole blood with IC 50 values in the nanomolar (290‐520 nmol/L) and low micromolar (1.0‐2.3 µmol/L) ranges, respectively. Sinapic acid and 2,5‐dihydroxy derivatives were more stable than CAPE in whole blood, and ketone analogues were degraded more slowly in HepaRG hepatocyte cultures than esters. All compounds underwent modification consistent with glucuronidation in HepaRG cultures as determined using LC‐MS/MS analysis, though the modified sinapoyl ketone ( 10) retained 50% of its inhibitory activity after up to one hour of incubation. This study has identified at least one CAPE analogue, compound 10 , that shows favorable properties that warrant further in vivo investigation as an antiinflammatory compound.