Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors

Dinh, Chau-Phi; Ville, Alexia; Neukirch, Konstantin; Viault, Guillaume; Temml, Veronika; Koeberle, Andreas; Werz, Oliver; Schuster, Daniela; Stuppner, Hermann; Richomme, Pascal; Hélesbeux, Jean-Jacques; Séraphin, Denis

doi:10.1016/j.ejmech.2020.112518

Cited by 10 publications

(19 citation statements)

References 33 publications

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“… 41 Both α- and β-forms ( 13a , 13b , 27a , 27b ) were obtained from the corresponding δ-forms of the garcinoic acid ( 13d ) and amplexichromanol ( 27d ) series through a two-step strategy, which involves the preparation of the mono- or bis-Mannich bases and their reduction with sodium cyanoborohydride. 42 , 43 δ-( Z )-Garcinoic acid 13e has been previously isolated from Clusia grandiflora , more specifically from fruits, and subsequently characterized. 44 In the current study, it was prepared from the corresponding alcohol 10e extracted from the stem barks of this plant and also found in G. amplexicaulis ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

et al. 2021

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Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol ( 27a ), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E 2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.

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Section: Resultsmentioning

confidence: 99%

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

et al. 2021

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“…While these mutations may affect the structure, test results showed that catalytic fidelity was conserved [ 30 ]. This crystallized structure was used by many groups as well as our group for molecular modeling [ 19 , 20 , 21 , 31 ]. Zileuton ( 1 ) and SAPE ( 2 ) were docked as references.…”

Section: Resultsmentioning

confidence: 99%

“…Unfortunately, all our attempts, whether with the first or the second method, failed to obtain dihydroxyl analogs. From the least substituted compound (11: R 2 -R 5 = H) to compounds variously substituted with hydroxyl and methoxy (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), a total of 21 hybrids were obtained in this subseries (Scheme 2). Structures of compounds were confirmed by NMR spectroscopy.…”

Section: Synthesismentioning

confidence: 99%

New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition

et al. 2020

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A novel series of zileuton-hydroxycinnamic acid hybrids were synthesized and screened as 5-lipoxygenase (5-LO) inhibitors in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Zileuton’s (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters’ ester linkage and phenolic acid moieties were investigated. Compound 28, bearing zileuton’s (1) benzo[b]thiophene and sinapic acid phenethyl ester’s (2) α,β-unsaturated phenolic acid moiety 28, was shown to be equipotent to zileuton (1), the only clinically approved 5-LO inhibitor, in stimulated HEK293 cells. Compound 28 was three times as active as zileuton (1) for the inhibition of 5-LO in PMNL. Compound 37, bearing the same sinapic acid (3,5-dimethoxy-4-hydroxy substitution) moiety as 28, combined with zileuton’s (1) hydroxyurea subunit was inactive. This result shows that the zileuton’s (1) benzo[b]thiophene moiety is essential for the inhibition of 5-LO product biosynthesis with our hydrids. Unlike zileuton (1), Compound 28 formed two π–π interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a π–π interaction with Phe177 which may play a part in product specificity as reported.

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“…[17,18] Recently, vitamin E derivatives, more specifically garcinoic acids, garcinamides and amplexichromanols, showed promising antiinflammatory properties (Figure 1). [19][20][21][22] On the other hand, a relatively poor antibacterial activity has been reported for either natural or synthetic T and T3 derivatives. [21][22][23][24][25][26] However, a synergistic antibacterial effect has been described when vitamin E is used in combination with antibiotics.…”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21][22] On the other hand, a relatively poor antibacterial activity has been reported for either natural or synthetic T and T3 derivatives. [21][22][23][24][25][26] However, a synergistic antibacterial effect has been described when vitamin E is used in combination with antibiotics. [27,28] In order to discover new antibacterial molecules based on vitamin E structure, this study aimed to semisynthesize new 5-substituted vitamin E derivatives and especially 6-hydroxychroman-5carboxylic acids, from T or T3 series, with or without terminal oxidized functions (allylic alcohol, diol or carboxylic acid), and to evaluate their antibacterial activity against resistant pathogens.…”

Section: Introductionmentioning

confidence: 99%

Semisynthetic Vitamin E Derivatives as Potent Antibacterial Agents against Resistant Gram‐Positive Pathogens

et al. 2020

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New 5‐substituted vitamin E derivatives were semisynthesized, and their antibacterial activity against human Gram‐positive and Gram‐negative pathogens was evaluated. Several vitamin E analogues were active against methicillin‐resistant Staphylococcus aureus (MRSA) and/or methicillin‐resistant Staphylococcus epidermidis (MRSE); structure‐activity relationships (SARs) are discussed. As a result, it is shown that the presence of a carboxylic acid function at the C‐5 position and/or at the end of the side chain is crucial for the antibacterial activity. The bactericidal or bacteriostatic action of three compounds against MRSA and MRSE was confirmed in a time‐kill kinetics study, and the cytotoxicity on human cells was evaluated. The preliminary mechanism study by confocal microscopy indicated that those vitamin E analogues led to bacterial cell death through membrane disruption.

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Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors

Cited by 10 publications

References 33 publications

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation

New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition

Semisynthetic Vitamin E Derivatives as Potent Antibacterial Agents against Resistant Gram‐Positive Pathogens

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