Caffeic Acid Phenethyl Ester Analogues as Selective Inhibitors of 12-Lipoxygenase Product Biosynthesis in Human Platelets

Hébert, Mathieu; Selka, Ayyoub; Lebel, Andréa A.; Chiasson, Audrey Isabel; Gauvin, Vanessa L.; Matthew, Alexis J.; Hébert, Martin; Doiron, Jérémie A.; Doucet, Marco S.; Touaibia, Mohamed; Surette, Marc E.; Boudreau, Luc H.

doi:10.2139/ssrn.4352842

Cited by 1 publication

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“…Human embryonic kidney 293 (HEK293) (CRL‐1573; ATCC) cells stably transfected with each of the three lipoxygenase enzymes were used to study the inhibitory activity of the test molecules. These cells are easily transfected to express lipoxygenase enzymes and have been a valuable tool to study the cell biology and molecular pharmacology of lipoxygenases (Allain et al, 2015; Chiasson et al, 2020; Doucet et al, 2019; Gerstmeier et al, 2014; Hébert et al, 2023; Mbarik et al, 2019; Touaibia et al, 2018). Preparation of HEK293 cells stably co‐expressing human 5‐LO and FLAP was previously described (Allain et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

“…Stimulations were stopped with 0.5 volume of cold CH 3 OH:CH 3 CN (1:1) containing 200 ng/mL each of prostaglandin B 2 (PGB 2 ; Cayman Chemicals) and 19‐OH PGB2 (Cayman Chemicals) as internal standards. Samples were stored at −20°C overnight then prepared for their subsequent LO product analysis using reversed‐phase high‐performance liquid chromatography (RP‐HPLC) as previously described (Robichaud et al, 2016) with modifications to the analytical system (Hébert et al, 2023). The 5‐LO products were comprised of the sum of LTB 4 , its trans isomers and 5‐hydroxyeicosatetraenoic acid (5‐HETE).…”

Section: Methodsmentioning

confidence: 99%

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Single and multiple inhibitors of the biosynthesis of 5‐, 12‐, 15‐lipoxygenase products derived from cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate: Synthesis and structure–activity relationship

Touaibia,

Chiasson,

Robichaud

et al. 2024

Drug Development Research

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The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure–activity study was carried out, which led to the discovery of several novel compounds (16a‐c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5‐, 12‐ and 15‐LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA‐approved 5‐LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α‐position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12‐ and 15‐LO products. Compounds 16a, 17a far surpassed baicalein, a known 12‐LO inhibitor, as inhibitors of 12‐LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α‐position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15‐LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5‐LO active site.

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