Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors

Lucia, Daniela De; Méndez‐Lucio, Oscar; Musio, Biagia; Bender, Andreas; Listing, Monika; Dennhardt, Sophie; Koeberle, Andreas; Garscha, Ulrike; Rizzo, Roberta; Manfredini, Stefano; Werz, Oliver; Ley, Steven V.

doi:10.1016/j.ejmech.2015.07.011

Cited by 31 publications

(26 citation statements)

References 36 publications

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“…Molecular docking was performed with AutoDock Vina 1.1.2 on 5‐LO (PDB code: 3O8Y) following the procedure outlined in “Design, synthesis and evaluation of semi‐synthetic triazole‐containing caffeic acid analogues as 5‐lipoxygenase inhibitors” by Daniela De Lucia et al. For optimization, the MMFF94 force field was used.…”

Section: Methodsmentioning

confidence: 99%

Sinapic acid phenethyl ester as a potent selective 5‐lipoxygenase inhibitor: Synthesis and structure–activity relationship

et al. 2018

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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 IC 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.

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Section: Methodsmentioning

confidence: 99%

Sinapic acid phenethyl ester as a potent selective 5‐lipoxygenase inhibitor: Synthesis and structure–activity relationship

et al. 2018

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“…The ester, 4‐(4,5‐diphenyl‐1 H ‐imidazol‐2‐yl)phenyl acetate ( 1 ), was prepared and isolated according to an adapted procedure, based on de Lucia et al A 50 mL single neck round‐bottomed flask containing 4‐(4,5‐diphenyl‐1 H ‐imidazol‐2‐yl)phenol ( 2 , 1.00 mmol, prepared according to the literature) was mixed with acetic anhydride (2.50 mmol) in PY (0.3 mL). After overnight stirring at room temperature, the content was diluted with 20 mL of dichloromethane and transferred to a separatory funnel.…”

Section: Methodsmentioning

confidence: 99%

The decomposition of triphenylimidazole‐para‐acetate follows specific base catalysis and can be conveniently followed by fluorescence

et al. 2019

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The kinetics of the decomposition reaction of 4-(4,5-diphenyl-1H-imidazol-2-yl)phenyl acetate (1) in basic alcoholic media was investigated, using a simple fluorescence (FL) spectrophotometric procedure. The process was conveniently studied using FL, since the triphenylimidazole-derived ester 1 and its reaction products (the corresponding phenol 2 and phenolate 2 − ) are all highly fluorescent (Φ FL > 37%). By carefully selecting excitation and emission wavelengths, observed rate constants k 1 in the order of 10 −3 to 10 −2 s −1 were obtained from either reactant consumption (λ ex = 300 nm, λ em = 400 nm) or product formation (λ ex = 350 nm, λ em = 475 nm); these were shown to be kinetically equivalent. Intensity-decay time profiles also gave a residual FL intensity parameter, shown to be associated to the distribution of produced species 2 and 2 − , according to the basicity of the medium. Studying the reaction in both methanol (MeOH) and isopropanol (iPrOH), upon addition of HO − , provided evidence that the solvent's conjugate base is the active nucleophilic species.When different bases were used (tBuO − , HO − , DBU and TEA), bimolecular rate constants k bim ranging from 4.5 to 6.5 L mol −1 s −1 were obtained, which proved to be non-dependent on the base pK aH , suggesting specific base catalysis for the decomposition of 1 in alcoholic media. KEYWORDS imidazole, kineticslight emissionlophine, rate constant 1 | INTRODUCTIONThe triphenylimidazole structural framework has been intensely studied throughout the years, by many different research groups, due to its fluorescence (FL) [1][2][3][4][5][6][7][8][9] and chemiluminescence (CL) [10][11][12][13][14][15][16][17][18][19][20][21][22] properties. The typical direct CL of 2,4,5-triphenylimidazole (also known as lophine) with oxygen in an alkaline media, first described by Radziszewski in 1877, [23] was studied mainly to elucidate its reaction mechanism. [11][12][13][18][19][20][21][22]24] However, lophine and its derivatives were also applied in other CL systems, being used as activators of the peroxyoxalate reaction [10] or enhancers of the luminol transformation. [25][26][27] In part, the vast array of application of these molecules, from FL to CL measurements, depends on the high FL quantum yields (Φ FL > 0.1) presented by them. [1][2][3][4][5][6][7][8][9][10]17,[24][25][26][27] In 1993, Kuroda et al. reported that triphenylimidazole-para-acetate (1, IUPAC name 4-(4,5-diphenyl-1H-imidazol-2-yl)phenyl acetate), as well as another three ester analogs based on pertinent fatty acids, could be applied on the evaluation of lipase activity through FL measurements. [8] Although ester 1 itself was not the most suitable for interaction with the lipase, it was primarily used to define the methodology for activity determination. Briefly, the method consisted on hydrolyzing the ester with the enzyme, followed by separation and FL

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“…Molecular docking was performed with AutoDock Vina 1.1.2 on 5‐LO (PDB code: 3O8Y) following a recently described procedure outlined in ‘Design, synthesis and evaluation of semi‐synthetic triazole‐containing caffeic acid analogues as 5‐lipoxygenase inhibitors’ by Daniela De Lucia et al. For optimization, the MMFF94 force field was used.…”

Section: Methodsmentioning

confidence: 99%

Structure–activity relationship of caffeic acid phenethyl ester analogs as new 5‐lipoxygenase inhibitors

et al. 2016

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Leukotrienes (LTs) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester (CAPE) possesses potent anti-LTs activity through the inhibition of 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of LTs. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5-LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties (4a-i and 5a-i, respectively) were synthesized by Sonogashira and Heck cross-coupling reactions to probe the effects of flexibility and aryl substitution on 5-LO inhibition. Caffeoyl alcohol and ethers (6, 7a-b) as well as caffeoyl aldehyde and ketones (8a-e) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers (IC of 10-30 μm). After preliminary anti-LTs activity screening in HEK293 cell models, 5-LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes (PMNL). Most screened compounds outperformed CAPE 3 in concentration-dependent assays on PMNL, with ester dimers 4i and 5i along with caffeoyl ethers 7a-b being roughly eight-, seven-, and 16-fold more potent than Zileuton, with IC values of 0.36, 0.43, and 0.18 μm, respectively.

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Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors

Cited by 31 publications

References 36 publications

Sinapic acid phenethyl ester as a potent selective 5‐lipoxygenase inhibitor: Synthesis and structure–activity relationship

Sinapic acid phenethyl ester as a potent selective 5‐lipoxygenase inhibitor: Synthesis and structure–activity relationship

The decomposition of triphenylimidazole‐para‐acetate follows specific base catalysis and can be conveniently followed by fluorescence

Structure–activity relationship of caffeic acid phenethyl ester analogs as new 5‐lipoxygenase inhibitors

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