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- Title
Sinapic acid phenethyl ester as a potent selective 5‐lipoxygenase inhibitor: Synthesis and structure–activity relationship.
- Authors
Touaibia, Mohamed; Hébert, Martin J. G.; Levesque, Natalie A.; Doiron, Jérémie A.; Doucet, Marco S.; Jean‐François, Jacques; Cormier, Marc; Boudreau, Luc H.; Surette, Marc E.
- Abstract
Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo®), currently the only approved and clinically used 5‐Lipoxygenase (5‐LO) inhibitor, the search for potent and safe 5‐LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5‐Lipoxygenase (5‐LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5‐LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β‐unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5‐LO in a concentration‐dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC50 of 0.3 μm, SAPE (10) was threefold more potent than CAPE (2) and 10‐fold more potent than zileuton (1), the only 5‐LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12‐lipoxygenase (12‐LO) and less effect on cyclooxygenase 1 (COX‐1) which makes it a more selective 5‐LO inhibitor. Sinapic acid phenethyl ester (SAPE, 10) inhibited 5‐lipoxygenase (5‐LO) in a concentration‐dependent manner and outperformed zileuton (1) (Zyflo®), currently the only approved and clinically used 5‐LO inhibitor. SAPE (10) had no effect on 12‐lipoxygenase and less effect on cyclooxygenase COX‐1 which makes it a more selective 5‐LO inhibitor. The presence of the two methoxy in positions 3 and 5 and the OH in position 4 in SAPE (10) seems to be an ideal configuration for inhibition of only 5‐LO.
- Subjects
LIPOXYGENASES; ESTERS; LEUKOTRIENE antagonists; CAFFEIC acid; ANTINEOPLASTIC agents; DRUG design
- Publication
Chemical Biology & Drug Design, 2018, Vol 92, Issue 5, p1876
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13360