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1.
Toxicon ; 201: 141-147, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34474068

RESUMO

Liriodenine is a biologically active plant alkaloid with multiple effects on mammals, fungi, and bacteria, but has never been evaluated for insecticidal activity. Accordingly, liriodenine was applied topically in ethanolic solutions to adult female Anopheles gambiae, and found to be mildly toxic. Its lethality was synergized in mixtures with dimethyl sulfoxide and piperonyl butoxide. Recordings from the ventral nerve cord of larval Drosophila melanogaster showed that liriodenine was neuroexcitatory and reversed the inhibitory effect of 1 mM GABA at effective concentrations of 20-30 µM. GABA antagonism on the larval nervous system was equally expressed on both susceptible and cyclodiene-resistant rdl preparations. Acutely isolated neurons from Periplaneta americana were studied under patch clamp and inhibition of GABA-induced currents with an IC50 value of about 1 µM were observed. In contrast, bicuculline did not reverse the effects of GABA on cockroach neurons, as expected. In silico molecular models suggested reasonable structural concordance of liriodenine and bicuculline and isosteric hydrogen bond acceptor sites. This study is the first assessing of the toxicology of liriodenine on insects and implicates the GABA receptor as one likely neuronal target, where liriodenine might be considered an active chemical analog of bicuculline.


Assuntos
Aporfinas , Inseticidas , Animais , Aporfinas/toxicidade , Drosophila melanogaster , Feminino , Inseticidas/toxicidade , Receptores de GABA
2.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361547

RESUMO

Essential oils of aromatic plants represent an alternative to classical pest control with synthetic chemicals. They are especially promising for the alternative control of stored product pest insects. Here, we tested behavioral and electrophysiological responses of the stored product pest Tribolium confusum, to the essential oil of a Brazilian indigenous plant, Varronia globosa, collected in the Caatinga ecosystem. We analyzed the essential oil by GC-MS, tested the effects of the entire oil and its major components on the behavior of individual beetles in a four-way olfactometer, and investigated responses to these stimuli in electroantennogram recordings (EAG). We could identify 25 constituents in the essential oil of V. globosa, with anethole, caryophyllene and spathulenole as main components. The oil and its main component anethole had repellent effects already at low doses, whereas caryophyllene had only a repellent effect at a high dose. In addition, the essential oil abolished the attractive effect of the T. confusum aggregation pheromone. EAG recordings revealed dose-dependent responses to the individual components and increasing responses to the blend and even more to the entire oil. Our study reveals the potential of anethole and the essential oil of V. globosa in the management of stored product pests.


Assuntos
Antenas de Artrópodes/fisiologia , Comportamento Animal/efeitos dos fármacos , Repelentes de Insetos , Magnoliopsida/química , Óleos Voláteis , Tribolium/fisiologia , Animais , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , Óleos Voláteis/química , Óleos Voláteis/farmacologia
3.
J Med Chem ; 64(15): 11496-11526, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34279935

RESUMO

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 ß-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.

4.
Phytochem Anal ; 32(6): 1102-1109, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33938065

RESUMO

INTRODUCTION: Xanthones are metabolites with a variety of biological properties. The Clusiaceae family, which until recently included the genus Calophyllum, is recognised for its production of monohydroxylated and polyhydroxylated xanthones. Presently, C. brasiliense is the only Calophyllum spp. known to occur in the Yucatan peninsula. OBJECTIVE: To use a combination of traditional phytochemical methods and carbon-13 nuclear magnetic resonance (13 C-NMR) dereplication analysis to identify xanthones in the stem bark of C. brasiliense. MATERIAL AND METHODS: Initial fractionation and purification of the stem bark extract of C. brasiliense produced macluraxanthone (1). Additional xanthones, together with chromanones and terpenoids, were identified using 13 C-NMR dereplication analysis in different semipurified fractions obtained from the low and medium polarity fractions of the stem bark extract of C. brasiliense. RESULTS: Initial identification of macluraxanthone (1) was confirmed by 13 C-NMR dereplication analysis; additionally, 13 C-NMR dereplication analysis allowed the identification of a number of monohydroxylated and polyhydroxylated xanthones, together with chromanones and terpenoids. CONCLUSION: This study confirms C. brasiliense as a rich source of xanthones and the 13 C-NMR dereplication analysis as a suitable method to quickly identify the presence of different families of secondary metabolites in semipurified fractions.


Assuntos
Calophyllum , Xantonas , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Casca de Planta , Extratos Vegetais
5.
Planta Med ; 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957699

RESUMO

The growing use of herbal medicines worldwide requires ensuring their quality, safety, and efficiency to consumers and patients. Quality controls of vegetal extracts are usually undertaken according to pharmacopeial monographs. Analyses may range from simple chemical experiments to more sophisticated but more accurate methods. Nowadays, metabolomic analyses allow a fast characterization of complex mixtures. In the field, besides mass spectrometry (MS), nuclear magnetic resonance spectroscopy (NMR) has gained importance in the direct identification of natural products in complex herbal extracts. For a decade, automated dereplication processes based on 13C-NMR have been emerging to efficiently identify known major compounds in mixtures. Though less sensitive than MS, 13C-NMR has the advantage of being appropriate to discriminate stereoisomers. Since NMR spectrometers nowadays provide useful datasets in a reasonable time frame, we have recently made available MixONat, a software that processes 13C as well as distortionless enhancement by polarization transfer (DEPT)-135 and -90 data, allowing carbon multiplicity (i.e., CH3, CH2, CH, and C) filtering as a critical step. MixONat requires experimental or predicted chemical shifts (δ C) databases and displays interactive results that can be refined based on the user's phytochemical knowledge. The present article provides step-by-step instructions to use MixONat starting from database creation with freely available and/or marketed δ C datasets. Then, for training purposes, the reader is led through a 30 - 60 min procedure consisting of the 13C-NMR based dereplication of a peppermint essential oil.

6.
ChemMedChem ; 16(5): 881-890, 2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33219748

RESUMO

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.

7.
Cancers (Basel) ; 12(11)2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33207594

RESUMO

Investigations of liver metastatic colonization suggest that the microenvironment is preordained to be intrinsically hospitable to the invasive cancer cells. To identify molecular determinants of that organotropism and potential therapeutic targets, we conducted proteomic analyses of the liver in an aggressive model of sarcomatoid peritoneal mesothelioma (M5-T1). The quantitative changes between SWATH-MS (sequential window acquisition of all theoretical fragmentation spectra) proteotype patterns of the liver from normal rats (G1), adjacent non-tumorous liver from untreated tumor-bearing rats (G2), and liver from curcumin-treated rats without hepatic metastases (G3) were compared. The results identified 12 biomarkers of raised immune response against M5-T1 cells in G3 and 179 liver biomarker changes in (G2 vs. G1) and (G3 vs. G2) but not in (G3 vs. G1). Cross-comparing these 179 candidates with proteins showing abundance changes related to increasing invasiveness in four different rat mesothelioma tumor models identified seven biomarkers specific to the M5-T1 tumor. Finally, analysis of correlations between these seven biomarkers, purine nucleoside phosphorylase being the main biomarker of immune response, and the 179 previously identified proteins revealed a network orchestrating liver colonization and treatment efficacy. These results highlight the links between potential targets, raising interesting prospects for optimizing therapies against highly invasive cancer cells exhibiting a sarcomatoid phenotype and sarcoma cells.

8.
Molecules ; 25(17)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887350

RESUMO

Alternaria dauci is the causal agent of Alternaria leaf blight (ALB) in carrot (Daucus carota) crops around the world. However, to date, A. dauci has received limited attention in its production of phytotoxic metabolites. In this investigation, the bioassay-guided isolation of the extract from liquid cultures of A. dauci resulted in the isolation of two metabolites identified as α-acetylorcinol (1) and p-hydroxybenzoic acid (2), based on their spectroscopic data and results from chemical correlation reactions. Testing of both metabolites in different assays showed an important phytotoxic activity for p-hydroxybenzoic acid (2) when tested in the leaf-spot assay on parsley (Petroselinum crispum), in the leaf infiltration assay on tobacco (Nicotiana alata) and marigold (Tagetes erecta), and in the immersion assay on parsley and parsnip (Pastinaca sativa) leaves. Quantification of the two metabolites in the crude extract of A. dauci kept at different times showed that p-hydroxybenzoic acid (2) is one of the first metabolites to be synthesized by the pathogen, suggesting that this salicylic acid derivative could play an important role in the pathogenicity of the fungus.


Assuntos
Alternaria/metabolismo , Metaboloma , Toxinas Biológicas/metabolismo , Piperazina/análise , Piperazina/química , Folhas de Planta/metabolismo , Metabolismo Secundário , Toxinas Biológicas/química
9.
Biomolecules ; 10(9)2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887413

RESUMO

Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1-4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1-4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.


Assuntos
Garcinia/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Compostos Policíclicos/farmacologia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acilação , Benzofenonas/química , Benzofenonas/isolamento & purificação , Benzofenonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fator de Transcrição GATA2/metabolismo , Humanos , Interferon gama/metabolismo , Complexo Principal de Histocompatibilidade/efeitos dos fármacos , Complexo Principal de Histocompatibilidade/genética , Proteínas de Membrana Transportadoras/metabolismo , Simulação de Acoplamento Molecular , Proteínas Nucleares/metabolismo , Floroglucinol/química , Floroglucinol/isolamento & purificação , Compostos Policíclicos/química , Compostos Policíclicos/isolamento & purificação , Prenilação , Cultura Primária de Células , Fator de Transcrição STAT1/metabolismo , Terpenos/química , Terpenos/farmacologia , Transativadores/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/química
10.
Anal Bioanal Chem ; 412(27): 7405-7416, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32851457

RESUMO

Alkaloids represent a major group of natural products (NPs), derived from highly diverse organisms. These structurally varied specialized metabolites are widely used for medicinal purposes and also known as toxic contaminants in agriculture and dietary supplements. While the detection of alkaloids is generally facilitated by GC- or LC-MS, these techniques do require considerable efforts in sample preparation and method optimization. Bypassing these limitations and also reducing experimental time, matrix-free laser desorption ionization (LDI) and related methods may provide an interesting alternative. As many alkaloids show close structural similarities to matrices used in matrix-assisted laser desorption ionization (MALDI), they should ionize upon simple laser irradiation without matrix support. With this in mind, the current work presents a systematic evaluation of LDI properties of a wide range of structurally diverse alkaloids. Facilitating a direct comparison between LDI and ESI-MS fragmentation, all tested compounds were further studied by electrospray ionization (ESI). Moreover, crude plant extracts of Atropa belladonna, Cinchona succirubra, and Colchicum autumnale were analyzed by LDI in order to evaluate direct alkaloid detection and dereplication from complex mixtures. Finally, dose-dependent evaluation of MALDI and LDI detection using an extract of Rosmarinus officinalis spiked with atropine, colchicine, or quinine was conducted. Overall, present results suggest that LDI provides a versatile analytical tool for analyzing structurally diverse alkaloids as single compounds and from complex mixtures. It may further serve various potential applications ranging from quality control to the screening for toxic compounds as well as the build up of MS databases. Graphical abstract.


Assuntos
Alcaloides/análise , Atropa belladonna/química , Cinchona/química , Colchicum/química , Extratos Vegetais/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
11.
Eur J Med Chem ; 202: 112518, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668380

RESUMO

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.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Desenho de Fármacos , Inibidores de Lipoxigenase/farmacologia , Vitamina E/análogos & derivados , Amidas/síntese química , Amidas/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Vitamina E/síntese química , Vitamina E/química , Vitamina E/farmacologia
12.
Anal Chem ; 92(13): 8793-8801, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32479074

RESUMO

Whether chemists or biologists, researchers dealing with metabolomics require tools to decipher complex mixtures. As a part of metabolomics and initially dedicated to identifying bioactive natural products, dereplication aims at reducing the usual time-consuming process of known compounds isolation. Mass spectrometry and nuclear magnetic resonance are the most commonly reported analytical tools during dereplication analysis. Though it has low sensitivity, 13C NMR has many advantages for such a study. Notably, it is nonspecific allowing simultaneous high-resolution analysis of any organic compounds including stereoisomers. Since NMR spectrometers nowadays provide useful data sets in a reasonable time frame, we have embarked upon writing software dedicated to 13C NMR dereplication. The present study describes the development of a freely distributed algorithm, namely MixONat and its ability to help researchers decipher complex mixtures. Based on Python 3.5, MixONat analyses a {1H}-13C NMR spectrum optionally combined with DEPT-135 and 90 data-to distinguish carbon types (i.e., CH3, CH2, CH, and C)-as well as a MW filtering. The software requires predicted or experimental carbon chemical shifts (δc) databases and displays results that can be refined based on user interactions. As a proof of concept, this 13C NMR dereplication strategy was evaluated on mixtures of increasing complexity and exhibiting pharmaceutical (poppy alkaloids), nutritional (rosemary extracts) or cosmetics (mangosteen peel extract) applications. Associated results were compared with other methods commonly used for dereplication. MixONat gave coherent results that rapidly oriented the user toward the correct structural types of secondary metabolites, allowing the user to distinguish between structurally close natural products, including stereoisomers.


Assuntos
Produtos Biológicos/química , Espectroscopia de Ressonância Magnética/métodos , Software , Algoritmos , Alcaloides/química , Isótopos de Carbono/química , Bases de Dados de Compostos Químicos , Garcinia mangostana/química , Garcinia mangostana/metabolismo , Papaver/química , Papaver/metabolismo , Extratos Vegetais/química , Rosmarinus/química , Rosmarinus/metabolismo
13.
J Agric Food Chem ; 68(3): 884-891, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31825610

RESUMO

Having a long history of traditional medicinal applications, Papaver somniferum is also known as a source of various pharmacologically highly active opiates. Consequently, their detection from plant extracts is an important analytical task and generally addressed by methods of GC-MS and LC-MS. However, opiates do also show structural similarities to matrix molecules used in matrix-assisted laser desorption ionization (LDI) and may therefore ionize upon simple laser irradiation. Following this analytical approach, the present work thoroughly evaluated the direct detection of opiates by matrix-free LDI in crude extracts of P. somniferum. The method facilitated the identification of 10 reported opiates by their molecular formulas without any chromatographic prepurification. Moreover, a principal component analysis based on LDI-MS data permitted the correct grouping of all extracts according to their inherent chemistry. Concluding experiments on serial dilutions of thebaine further evaluated potential quantitative applications of the method. Overall results highlight the promising potential of LDI-MS for the swift detection of opiates in complex mixtures.


Assuntos
Alcaloides Opiáceos/química , Papaver/química , Extratos Vegetais/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Lasers , Estrutura Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação
14.
Front Pharmacol ; 10: 378, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031626

RESUMO

Mycobacterium ulcerans is the bacillus responsible for Buruli ulcer, an infectious disease and the third most important mycobacterial disease worldwide, after tuberculosis and leprosy. M. ulcerans infection is a type of panniculitis beginning mostly with a nodule or an oedema, which can progress to large ulcerative lesions. The lesions are caused by mycolactone, the polyketide toxin of M. ulcerans. Mycolactone plays a central role for host colonization as it has immunomodulatory and analgesic effects. On one hand, mycolactone induces analgesia by targeting type-2 angiotensin II receptors (AT2R), causing cellular hyperpolarization and neuron desensitization. Indeed, a single subcutaneous injection of mycolactone into the mouse footpad induces a long-lasting hypoesthesia up to 48 h. It was suggested that the long-lasting hypoesthesia may result from the persistence of a significant amount of mycolactone locally following its injection, which could be probably due to its slow elimination from tissues. To verify this hypothesis, we investigated the correlation between hypoesthesia and mycolactone bioavailability directly at the tissue level. Various quantities of mycolactone were then injected in mouse tissue and hypoesthesia was recorded with nociception assays over a period of 48 h. The hypoesthesia was maximal 6 h after the injection of 4 µg mycolactone. The basal state was reached 48 h after injection, which demonstrated the absence of nerve damage. Surprisingly, mycolactone levels decreased strongly during the first hours with a reduction of 70 and 90% after 4 and 10 h, respectively. Also, mycolactone did not diffuse in neighboring skin tissue and only poorly into the bloodstream upon direct injection. Nevertheless, the remaining amount was sufficient to induce hypoesthesia during 24 h. Our results thus demonstrate that intact mycolactone is rapidly eliminated and that very small amounts of mycolactone are sufficient to induce hypoesthesia. Taken together, our study points out that mycolactone ought to be considered as a promising analgesic.

15.
J Nat Prod ; 82(1): 51-58, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30629440

RESUMO

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.


Assuntos
Garcinia/metabolismo , Tocotrienóis/metabolismo , Tocotrienóis/isolamento & purificação
16.
Nat Prod Res ; 33(15): 2182-2191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30375240

RESUMO

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.


Assuntos
Alcaloides/isolamento & purificação , Extratos Vegetais/química , Pirrolidinas/isolamento & purificação , Senécio/química , Alcaloides/química , Pirrolidinas/química , Análise Espectral/métodos
17.
Mar Drugs ; 18(1)2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31906052

RESUMO

Mycosporine-like amino acids (MAAs) are water-soluble metabolites, reported to exhibit strong UV-absorbing properties. They have been found in a wide range of marine organisms, especially those that are exposed to extreme levels of sunlight, to protect them against solar radiation. In the present study, the absolute configuration of 14 mycosporine-like-amino acids was determined by combining the results of electronic circular dichroism (ECD) experiments and that of advanced Marfey's method using LC-MS. The crystal structure of a shinorine hydrate was determined from single crystal X-ray diffraction data and its absolute configuration was established from anomalous-dispersion effects. Furthermore, the anti-aging and wound-healing properties of these metabolites were evaluated in three different assays namely the inhibition of collagenase, inhibition of advanced glycation end products (AGEs) and wound healing assay (scratch assay).


Assuntos
Aminoácidos/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Aminoácidos/química , Dicroísmo Circular , Colagenases/efeitos dos fármacos , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Humanos , Técnicas In Vitro , Difração de Raios X
18.
Fitoterapia ; 131: 182-188, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30339926

RESUMO

Secondary metabolites from lichens are known for exhibiting various biological effects such as anti-inflammatory, antioxidant and antibacterial activities. Despite this wide range of reported biological effects, their impact on the formation of advanced glycation end products (AGEs) remains vastly unexplored. The latter are known contributors to lifestyle and age-related diseases such as Alzheimer and Parkinson. Moreover, the development of atherosclerosis and arterial stiffness is causally linked to the formation of AGEs. With this in mind, the present work evaluated the inhibitory effects of secondary lichen metabolites on the formation of pentosidine-like AGEs' by using an in vitro, Maillard reaction based, fluorescence assay. Overall, thirty-seven natural and five synthetically modified compounds were tested, eighteen of which exhibiting IC50 values in the range of 0.05 to 0.70 mM. This corresponds to 2 to 32 fold of the inhibitory activity of aminoguanidine. Targeting one major inhibiting mechanism of AGEs formation, all compounds were additionally evaluated on their radical scavenging capacities in an DPPH assay. Furthermore, as both AGEs' formation and hypertension are major risk factors for atherosclerosis, compounds that were available in sufficient amounts were also tested for their vasodilative effects. Overall, and though some of the active compounds were previously reported cytotoxic, present results highlight the interesting potential of secondary lichen metabolites as anti-AGEs and vasodilative agents.


Assuntos
Produtos Biológicos/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Líquens/química , Vasodilatadores/farmacologia , Animais , Produtos Biológicos/isolamento & purificação , Masculino , Estrutura Molecular , Ratos Endogâmicos WKY , Metabolismo Secundário , Vasodilatadores/isolamento & purificação
19.
Fitoterapia ; 131: 59-64, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30321650

RESUMO

Usually isolated from Garcinia (Clusiaceae) or Hypericum (Hypericaceae) species, some Polycyclic Polyprenylated AcylPhloroglucinols (PPAPs) have been recently reported as potential research tools for immunotherapy. Aiming at exploring the chemodiversity of PPAPs amongst Garcinia genus, a dereplication process suitable for such natural compounds has been developed. Although less sensitive than mass spectrometry, NMR spectroscopy is perfectly reproducible and allows stereoisomers distinction, justifying the development of 13C-NMR strategies. Dereplication requires the use of databases (DBs). To define if predicted DBs were accurate enough as dereplication tools, experimental and predicted δC of natural products usually isolated from Clusiaceae were compared. The ACD/Labs commercial software allowed to predict 73% of δC in a 1.25 ppm range around the experimental values. Consequently, with these parameters, the major PPAPs from a Garcinia bancana extract were successfully identified using a predicted DB.


Assuntos
Garcinia/química , Floroglucinol/isolamento & purificação , Extratos Vegetais/química , Bases de Dados de Compostos Químicos , Espectroscopia de Ressonância Magnética , Compostos Fitoquímicos/isolamento & purificação
20.
Nat Commun ; 9(1): 3834, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237488

RESUMO

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.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inflamação/patologia , Vitamina E/metabolismo , Adolescente , Adulto , Idoso , Animais , Araquidonato 5-Lipoxigenase/química , Hiper-Reatividade Brônquica/patologia , Sobrevivência Celular/efeitos dos fármacos , Sistema Livre de Células , Humanos , Concentração Inibidora 50 , Leucócitos/metabolismo , Inibidores de Lipoxigenase/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metaboloma , Camundongos , Pessoa de Meia-Idade , Peritonite/patologia , Proteínas Recombinantes/metabolismo , Vitamina E/química , Adulto Jovem
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