Sinapic acid is found in many edible
plants and fruits, such as
rapeseed, where it is the predominant phenolic compound. New sinapic
acid phenethyl ester (SAPE) analogues were synthesized and screened
as inhibitors of the biosynthesis of 5-lipoxygenase (5-LO) in stimulated
HEK293 cells and polymorphonuclear leukocytes (PMNL). Inhibition of
leukotriene biosynthesis catalyzed by 5-LO is a validated therapeutic
strategy against certain inflammatory diseases and allergies. Unfortunately,
the only inhibitor approved to date has limited clinical use because
of its poor pharmacokinetic profile and liver toxicity. With the new
analogues synthesized in this study, the role of the phenolic moiety,
ester function, and bioisosterism was investigated. Several of the
34 compounds inhibited the biosynthesis of 5-LO products, and 20 compounds
were 2–11 times more potent than zileuton in PMNL, which are
important producers of 5-LO products. Compounds 5i (IC50: 0.20 μM), 5l (IC50: 0.20
μM), and 5o (IC50: 0.21 μM) bearing
4-trifluoromethyl, methyl, or methoxy substituent at meta-position of the phenethyl moiety were 1.5 and 11.5 times more potent
than SAPE (IC50: 0.30 μM) and zileuton (IC50: 2.31 μM), respectively. Additionally, compound 9 (IC50: 0.27 μM), which was obtained after acetylation
of the 4-hydroxyl of SAPE, was equivalent to SAPE and 8 times more
active than zileuton. Furthermore, compound 20b (IC50: 0.27 μM) obtained after the bioisosteric replacement
of the ester function of SAPE by the 1,2,4-oxadiazole heterocycle
was equivalent to SAPE and 8 times more active than zileuton. Thus,
this study provides a basis for the rational design of new molecules
that could be developed further as anti 5-LO therapeutics.
Leukotrienes are biosynthesized by the conversion of arachidonic acid by 5-Lipoxygenase and play a key role in many inflammatory disorders. Inspired by caffeic acid phenylethyl ester (CAPE) (2) and an analog carrying a triazole substituted by cinnamoyl and 5-LO inhibitors recently reported by our team, sixteen new CAPE analogs bearing substituted triazole were synthesized by copper catalyzed Huisgen 1,3-dipolar cycloaddition. Compound 10e, an analog bearing p-CF3 phenethyl substituted triazole, was equivalent to CAPE (2) but clearly surpassed Zileuton (2), the only approved 5-LO inhibitor. Substitution of the phenethyl moiety by cyclohexylethyl, as with 12g, clearly increased 5-LO inhibition which confirms the importance of hydrophobic interactions. Molecular docking revealed new hydrogen bonds and π-π interactions between the enzyme and some of the investigated compounds. Overall, this work highlights the relevance of exploring polyphenolic compounds as leukotrienes biosynthesis inhibitors.
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