Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that ...long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13'-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13'-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
Advanced glycation end-products (AGEs) are involved in the pathogenesis of numerous diseases. Among them, cellular accumulation of AGEs contributes to vascular complications in diabetes. Besides ...using drugs to lower blood sugar, a balanced diet and the intake of herbal products potentially limiting AGE formation could be considered beneficial for patients' health. The current paper presents a simple and cheap high-throughput screening (HTS) assay based on AGE fluorescence and suitable for plant extract screening. We have already implemented an HTS assay based on vesperlysines-like fluorescing AGEs quickly (24 h) formed from BSA and ribose under physiological conditions. However, interference was noted when fluorescent compounds and/or complex mixtures were tested. To overcome these problems and apply this HTS assay to plant extracts, we developed a technique for systematic quantification of both vesperlysines (λ(exc) 370 nm; λ(em) 440 nm) and pentosidine-like (λ(exc) 335 nm; λ(em) 385 nm) AGEs. In a batch of medicinal and food plant extracts, hits were selected as soon as fluorescence decreased under a fixed threshold for at least one wavelength. Hits revealed during this study appeared to contain well-known and powerful anti-AGE substances, thus demonstrating the suitability of this assay for screening crude extracts (0.1 mg/mL). Finally, quercetin was found to be a more powerful reference compound than aminoguanidine in such assay.
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 E2 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.
Recent studies have highlighted the biological potential of tocotrienols, a vitamin E subfamily. The major natural sources of tocotrienols are complex mixtures requiring particularly challenging ...purification processes. The present study describes efficient semi-synthetic strategies toward relevant δ-(R)-tocotrienol derivatives, using as a starting material δ-(R)-garcinoic acid, the major vitamin E derivative isolated from Garcinia kola nuts, a renewable vegetal source.
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•Concise semisynthetic route to phenazine-vitamin E hybrids.•IBX regio and chemoselective oxidation in vitamin E series.•Efficient IBX mediated tocopheryl ortho-quinone formation.
A ...regioselective method for the semisynthesis of phenazine derivatives has been disclosed through an efficient IBX mediated ortho-quinone formation from vitamin E derivatives. High chemo- and regio-selectivity was observed during the oxidation step and the corresponding 5,6-ortho-quinones could react with various phenylenediamines. Thus, this methodology proves its interest as a concise semisynthetic pathway to phenazine-vitamin E hybrids with moderate to good yields.
Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from ...arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring.
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•A semi-quantitative computational workflow predicted 5-LO inhibitory activity.•24 garcinamides were selected for semisynthesis based on their predicted pIC50.•46% of the measured pIC50 values were consistent with the predicted ones.•Some new 5-LO inhibitors were more potent than their parents in cell-based assays.
Alkaloids and phenolic compounds are among the most biologically active natural products from the Jacobaea/Senecio genera (Asteraceae). To isolate original natural products directly from Jacobaea ...gigantea crude polar extracts, centrifugal partition chromatography (CPC) was used. Previously, we reported the phytochemical study of J. gigantea (syn. Senecio giganteus) n-butanol extract using various classical chromatographical techniques combined with CPC. Herein major constituents from the J. gigantea crude ethyl acetate extract and further compounds from the n-butanol extract were purified in only one step using this technique. A new pyrrolidine alkaloid, named senecipyrrolidine was isolated along with thirteen known compounds - chiro-inositol, three phenolic acids, six flavonoids, two quinones and emiline, another pyrrolidine alkaloid - from crude n-butanol or ethyl acetate extracts. Pyrrolidine alkaloids were isolated for the first time in the Jacobaea/Senecio genera and were probably biogenetically related to the two isolated quinones derivatives jacaranone and 3a-hydroxy-3,3a,7,7a-tetrahydrobenzofuran-2,6-dione, isolated in this species.
Through dereplication analysis, seven known Mammea coumarins were identified in a fraction obtained from Mammea neurophylla dichloromethane bark extract selected for its ability to prevent advanced ...glycation end-product (AGE) formation. Among them, a careful examination of the NMR dataset of pedilanthocoumarin B led to a structural revision. Inspection of LC-DAD-MS(n) chromatograms allowed us to predict the presence of four new compounds, which were further isolated. Using spectroscopic methods (¹H-, (13)C- and 2D-NMR, HRMS, UV), these compounds were identified as new benzoyl substituted 4-phenylcoumarins (iso-pedilanthocoumarin B and neurophyllol C) and 4-(1-acetoxypropyl)coumarins cyclo F (ochrocarpins H and I).
Naturally occurring substances are valuable resources for drug development. In this respect, chalcones are known to be antiproliferative agents against prostate cancer cell lines through various ...mechanisms or targets. Based on the literature and preliminary results, we aimed to study and optimise the efficiency of a series of chalcones to inhibit androgen-converting AKR1C3, known to promote prostate cancer. A total of 12 chalcones with different substitution patterns were synthesised. Structure-activity relationships associated with these modifications on AKR1C3 inhibition were analysed by performing enzymatic assays and docking simulations. In addition, the selectivity and cytotoxicity of the compounds were assessed. In enzymatic assays, C-6' hydroxylated derivatives were more active than C-6' methoxylated derivatives. In contrast, C-4 methylation increased activity over C-4 hydroxylation. Docking results supported these findings with the most active compounds fitting nicely in the binding site and exhibiting strong interactions with key amino acid residues. The most effective inhibitors were not cytotoxic for HEK293T cells and selective for 17β-hydroxysteroid dehydrogenases not primarily involved in steroid hormone metabolism. Nevertheless, they inhibited several enzymes of the steroid metabolism pathways. Favourable substitutions that enhanced AKR1C3 inhibition of chalcones were identified. This study paves the way to further develop compounds from this series or related flavonoids with improved inhibitory activity against AKR1C3.
Semi-synthesis of 5- and 7-formyltocopherols and tocotrienols has been developed by ortho-formylation of C-5 or C-7-unsubstituted vitamin E derivatives (14 examples) up to 90% yield, through heating ...in the presence of respectively 10-10-15 equivalents of MgCl2-Et3N-(CH2O)n. Formylation of 5-bromo-δ-tocotrienol revealed an unprecedented 5-bromo/7-formyl exchange and yielded 7-bromo-5-formyl-δ-tocotrienol as major product. The minor 5-bromo-7-formyl-δ-tocotrienol led in three steps to 7-formyl-δ-tocotrienol previously isolated from the stem bark of Garcinia virgata.
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