RESUMEN
In this work, the oxidation of theaflavin-3-gallate (TF-3-G) was investigated using (-)-epicatechin (EC) and (-)-epigallocatechin gallate (EGCG) as substrates in a one-pot reaction. The resulting TF-3-G oxidation product was acquired by employing acetonitrile/water and ethanol/water as eluents, respectively, which was identified as theanaphthoquinone-3'-gallate (TNQ-3'-G). Surprisingly, we discovered that TNQ-3'-G could react with certain protic solvents to form new and unstable complexes through intermolecular hydrogen bond. This reactivity was also confirmed by the presence of irregular peaks in reverse-phase high-performance liquid chromatography (RP-HPLC) besides spectroscopic data. Therefore, we inferred that the number of carboxyl groups may increase through the successive oxidative polymerization of the TFs oxidation products. The high-molecular polymer could also interact with biomacromolecules in a similar manner to their interaction with protic solvents. This interaction might be one of the main factors contributing to the broad hump of thearubigins (TRs) on the RP-HPLC baseline. Additionally, these findings lay a solid foundation for interpreting the structures of TRs and understanding their generation mechanism.
Asunto(s)
Biflavonoides , Catequina , Oxidación-Reducción , Biflavonoides/química , Biflavonoides/síntesis química , Catequina/química , Catequina/análogos & derivados , Catequina/síntesis química , Catequina/metabolismo , Cromatografía Líquida de Alta Presión , Solventes/química , Ácido Gálico/análogos & derivadosRESUMEN
The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure-activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC50 = 15.3, 27.2, 15.9 µM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.
Asunto(s)
Antiparasitarios/química , Antiparasitarios/farmacología , Benzofuranos/química , Biflavonoides/síntesis química , Chalconas/síntesis química , Indoles/química , Biflavonoides/química , Chalconas/química , Fenómenos Químicos , Técnicas de Química Sintética , Humanos , Leishmania infantum , Estructura Molecular , Relación Estructura-ActividadRESUMEN
In this research, sorghum procyanidins (PCs) and procyanidin B1 (PB1) were encapsulated in gelatin (Gel) to form nanoparticles as a strategy to maintain their stability and bioactivity and for possible applications as inhibitors of metalloproteinases (MMPs) of the gelatinase type. Encapsulation was carried out by adding either PCs or PB1 to an aqueous solution of A- or B-type Gel (GelA or GelB) at different concentrations and pH. Under this procedure, the nanoparticles PCs-GelA, PCs-GelB, PB1-GelA, and PB1-GelB were synthesized and subsequently characterized by experimental and computational methods. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that all types of nanoparticles had sizes in the range of 22-138 nm and tended to adopt an approximately spherical morphology with a smooth surface, and they were immersed in a Gel matrix. Spectral analysis indicated that the nanoparticles were synthesized by establishing hydrogen bonds and hydrophobic interactions betweenGel and the PCs or PB1. Study of simulated gastrointestinal digestion suggested that PCs were not released from the Gel nanoparticles, and they maintained their morphology (SEM analysis) and antioxidant activity determined by Trolox-equivalent antioxidant capacity (TEAC) assay. Computational characterization carried out through molecular docking studies of PB1 with Gel or (pro-)metalloproteinase-2 [(pro-)MMP-2], as a model representative of the PCs, showed very favorable binding energies (around -5.0 kcal/mol) provided by hydrogen bonds, van der Waals interactions, and desolvation. Additionally, it was found that PB1 could act as a selective inhibitor of (pro-)MMP-2.
Asunto(s)
Biflavonoides/química , Catequina/química , Gelatina/química , Nanopartículas/química , Proantocianidinas/química , Sorghum/química , Biflavonoides/síntesis química , Catequina/síntesis química , Gelatina/síntesis química , Modelos Moleculares , Estructura Molecular , Tamaño de la Partícula , Proantocianidinas/síntesis químicaRESUMEN
Procyanidins are polyphenols with antioxidant, anti-obesity, and anti-inflammatory properties. Procyanidin B2 (PCB2) gallate; specifically, PCB2 3,3â³-di-O-gallate (PCB2DG), inhibits cytokine production in T cells. However, the molecular interactions and partners of PCB2DG underlying this suppression of cytokine production are unclear. The present study aimed to elucidate mechanisms underlying regulation of tumor necrosis factor (TNF)-α production by PCB2DG. We found that production of TNF-α and glycolytic activity in activated CD4+ T cells were suppressed by PCB2DG treatment. The inhibition of TNF-α production was found to be mediated by mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1 (HIF-1) pathway, as PCB2DG suppressed the expression of HIF-1α, p-mTOR, and p-p70S6K (a downstream of the mTOR complex, mTORC1). Moreover, suppression of TNF-α production was mediated by regulation of the glycolytic enzyme lactate dehydrogenase at the posttranscriptional level. These results suggest that PCB2DG regulates TNF-α production by inhibiting glycolytic activity via the mTOR-HIF-1 pathway.
Asunto(s)
Biflavonoides/farmacología , Catequina/farmacología , Glucólisis/efectos de los fármacos , Factor 1 Inducible por Hipoxia/metabolismo , Proantocianidinas/farmacología , Linfocitos T/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Biflavonoides/síntesis química , Biflavonoides/química , Western Blotting , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Catequina/síntesis química , Catequina/química , Células Cultivadas , Citocinas/biosíntesis , Citocinas/genética , L-Lactato Deshidrogenasa/metabolismo , Ratones Endogámicos C57BL , Proantocianidinas/síntesis química , Proantocianidinas/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Linfocitos T/citología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Redox-active quinones have been reported to show good potential for biological activities, while efforts are directed to explore the usefulness of these materials further in cancer management. Our previous study demonstrated that theaflavin and theaflavin-gallates (tea-extracted polyphenols) selectively induce apoptosis of tumour cells in vitro, but its concentration for showing half-maximal therapeutic response remains a matter of concern. In this report, we demonstrated that if theaflavin is conjugated with gold nanoparticles (AuNPs) to form a nanoconjugate AuNP@TfQ, its apoptotic ability increases significantly in comparison to the bare theaflavin (Tf). The nanoconjugate is prepared by following a one-step green synthesis ̶ a reaction between HAuCl4 and the aflavin at room temperature. AuNP@TfQ is characterized using particle size analysis, FESEM, UV-vis, FTIR, fluorescence, and X-ray photoelectron spectroscopytechniques. We assume that the enhanced anti-cancer effect of AuNP@TfQ appears due to the facile oxidation of the pristine theaflavin to its quinone derivative on the surface of AuNPs. The presence of quinone motif in AuNP@TfQ induces an increased level of ROS generation probably through the depolarization of mitochondria and resulted in the caspase-mediated apoptotic cell death which may hold the potential for a "magic bullet"-mediated ovarian cancer treatment.
Asunto(s)
Biflavonoides/farmacología , Catequina/farmacología , Oro/farmacología , Nanopartículas del Metal/química , Neoplasias Ováricas/patología , Apoptosis/efectos de los fármacos , Biflavonoides/síntesis química , Biflavonoides/química , Biomarcadores de Tumor/metabolismo , Catequina/síntesis química , Catequina/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Femenino , Hemólisis/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Espectroscopía de Fotoelectrones , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Reactive oxygen species (ROS) are known to be produced during the amyloid beta (Aß) aggregation process. Both ROS production and Aß fibril formation can result in nerve cell injury. Proanthocyanidins are oligomers of catechin that can act as inhibitors of Aß aggregation. Procyanidin B3 (Cat-Cat), the dimer of (+)-catechin, can easily cross the blood-brain barrier. Previously, we synthesized two derivatives of Cat-Cat, namely Cat-PCat and PCat-PCat, in which the geometry of one or both catechin molecules in Cat-Cat was constrained to be planar. The antioxidative activities of Cat-PCat and PCat-PCat were found to be stronger than that of Cat-Cat, with PCat-PC at exhibiting the most potent activity. These compounds are predicted to protect against Aß-induced neurotoxicity via inhibition of Aß aggregation as well as by antioxidative effects toward Aß-induced intracellular ROS generation. PCat-PCat exhibited the most potent neuroprotective effects against Aß-induced cytotoxicity, which resulted from inhibition of ß-sheet structure formation during the Aß aggregation process. PCat-PCat may be a promising lead compound for the treatment of Alzheimer's disease.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Antioxidantes/farmacología , Biflavonoides/farmacología , Catequina/farmacología , Fármacos Neuroprotectores/farmacología , Proantocianidinas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Antioxidantes/síntesis química , Antioxidantes/química , Biflavonoides/síntesis química , Biflavonoides/química , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Catequina/síntesis química , Catequina/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Proantocianidinas/síntesis química , Proantocianidinas/química , Agregado de Proteínas/efectos de los fármacos , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
Polymeric procyanidins (PPCs) were the major constituents of procyanidins, while they have poor bioactivity. To better utilize PPCs, a semisynthetic approach for converting PPCs to oligomeric procyanidins (OPCs) was proposed. Grape seed PPCs were simultaneously reacted with catechin (C) and epicatechin (EC) under acid condition. Combining response surface methodology (RSM) and single-factor experiments, an optimized semisynthetic condition was confirmed with the ratio of PPCs with C and EC of 1:1:1, temperature of 40⯰C, reaction time of 20â¯min and 0.1â¯M methanolic HCl. High-speed counter-current chromatography (HSCCC) was adopted to obtain three fractions from semisynthetic products and preparative-HPLC was used to isolate individual procyanidins. Thirteen B-type procyanidins including monomers, dimers and trimers were got with high yield of 0.8-17.8â¯mg from 200â¯mg semisynthetic products and high purity over 91%. The developed semisynthesis combined with separation method was efficient to obtain individual OPCs in preparative scale.
Asunto(s)
Biflavonoides/química , Catequina/química , Proantocianidinas/química , Vitis/química , Biflavonoides/análisis , Biflavonoides/síntesis química , Catequina/análisis , Catequina/síntesis química , Cromatografía Líquida de Alta Presión , Distribución en Contracorriente , Dimerización , Extractos Vegetales/química , Polimerizacion , Proantocianidinas/análisis , Proantocianidinas/síntesis química , Semillas/química , Semillas/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Vitis/metabolismoRESUMEN
PURPOSE: Flavonoids are a group of secondary metabolites of the polyphenols class present in several plant species. Among them, the biflavonoid agathisflavone is of interest since it bears several biological effects that include: antiviral, antitumoral, antiprotozoal and neurogenic actions. In this sense, this study aims to use the important tool of scientific prospecting to assess the level of research development concerning the flavonoid agathisflavone. METHODS: The experimental design was carried out through strategic reach with keywords on the PubMed (National Center for Biotechnology Information - NCBI) and Science Direct platforms. The articles were compiled and exported to Microsoft Office Excel 2007, where they were analyzed, stored and distributed in charts organized as to different countries, year of publication of scientific articles and journals RESULTS: The prospective research resulted in the identification of 81 scientific productions, published in several journals, submitted by different countries, in several areas of medical domain and in different years of publication over the last 50 years (1965 - 2018). It was also possible to investigate the advances in the study of agathisflavone for the development of new therapeutics. CONCLUSION: Although agathisflavone has been known in the literature since at least 1969, only 23 of the eligible articles found evaluated its possible therapeutic effects. The demonstrated biological activities of agathisflavone range from antiprotozoal to neurogenesis and neuroprotection, however, the molecule needs to be better studied at the in vivo and human level.
Asunto(s)
Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Antiprotozoarios/farmacología , Biflavonoides/farmacología , Fármacos Neuroprotectores/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Biflavonoides/síntesis química , Biflavonoides/química , Diseño de Fármacos , Humanos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estudios ProspectivosRESUMEN
Natural A-type procyanidins have shown very interesting biological activities, such as their proven antiadherence properties against pathogenic bacteria. In order to find the structural features responsible for their activities, we describe herein the design and synthesis of six A-type procyanidin analogues and the evaluation of their antimicrobial and antibiofilm properties against 12 resistant bacteria, both Gram positive and Gram negative, isolated from organic foods. The natural A-type procyanidin A-2, which had known antiadherence activity, was also tested as a reference compound for the comparative studies. Within the series, analogue 4, which had a NO2 group on ring A, showed the highest antimicrobial activity (MIC of 10 µg/mL) and was one of the best molecules at preventing biofilm formation (up to 40% decreases at 100 µg/mL) and disrupting preformed biofilms (up to 40% reductions at 0.1 µg/mL). Structure-activity relationships are also analyzed.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Biflavonoides/farmacología , Biopelículas/efectos de los fármacos , Catequina/farmacología , Proantocianidinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Fenómenos Fisiológicos Bacterianos/efectos de los fármacos , Biflavonoides/síntesis química , Biflavonoides/química , Catequina/síntesis química , Catequina/química , Microbiología de Alimentos , Pruebas de Sensibilidad Microbiana , Proantocianidinas/síntesis química , Proantocianidinas/químicaRESUMEN
Proanthocyanidins, also known as condensed tannins or oligomeric flavonoids, are found in many edible plants and exhibit interesting biological activities. Herein, we report a new, simple method for the stereoselective synthesis of procyanidin B6, a (+)-catechin-(4-6)-(+)-catechin dimer, by Lewis acid-catalyzed intramolecular condensation. The 5-O-t-butyldimethylsilyl (TBDMS) group of 5,7,3'4'-tetra-O-TBDMS-(+)-catechin was regioselectively removed using trifluoroacetic acid, leading to the "regio-controlled" synthesis of procyanidin B6. The 5-hydroxyl group of the 7,3',4'-tri-O-TBDMS-(+)-catechin nucleophile and the 3-hydroxyl group of 5,7,3',4'-tetra-O-benzylated-(+)-catechin electrophile were connected with an azelaic acid. The subsequent SnCl4-catalyzed intramolecular condensation proceeded smoothly to give the 4-6-condensed catechin dimer. This is the first report on the complete regioselective synthesis of a 4-6-connected oligomer without modifying the 8-position.
Asunto(s)
Biflavonoides/síntesis química , Catequina/síntesis química , Proantocianidinas/síntesis química , Acetilación , Biflavonoides/química , Catequina/química , Dimerización , Estructura Molecular , Proantocianidinas/químicaRESUMEN
Proanthocyanidins are oligomers of catechins that exhibit potent antioxidative activity and inhibit binding of oxidized low-density lipoprotein (OxLDL) to the lectin-like oxidized LDL receptor (LOX-1), which is involved in the onset and development of arteriosclerosis. Previous attempts aimed at developing proanthocyanidin derivatives with more potent antioxidative activity and stronger inhibition for LOX-1 demonstrated the synthesis of a novel proanthocyanidin derivative (1), in which the geometry of one catechin molecule in procyanidin B3 was constrained to a planar orientation. The radical scavenging activity of 1 was 1.9-fold higher than that of procyanidin B3. Herein, we synthesized another procyanidin B3 analogue (2), in which the geometries of both catechin molecules in the dimer were constrained to planar orientations. The radical scavenging activity of 2 was 1.5-fold higher than that of 1, suggesting that 2 may be a more effective candidate than 1 as a therapeutic agent to reduce oxidative stress induced in arteriosclerosis or related cerebrovascular disease.
Asunto(s)
Biflavonoides/química , Catequina/química , Depuradores de Radicales Libres/química , Proantocianidinas/química , Biflavonoides/síntesis química , Biflavonoides/metabolismo , Catequina/síntesis química , Catequina/metabolismo , Dimerización , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/metabolismo , Humanos , Cinética , Lipoproteínas LDL/antagonistas & inhibidores , Lipoproteínas LDL/metabolismo , Proantocianidinas/síntesis química , Proantocianidinas/metabolismo , Receptores Depuradores de Clase E/antagonistas & inhibidores , Receptores Depuradores de Clase E/metabolismoRESUMEN
Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids. Preliminary studies established that the strategy could also be successfully extended to the preparation of very rare triflavonoids, which are also expected to be useful tools for biological intervention. Prompted by previous inhibitory studies with flavonoid libraries, amyloid anti-aggregation screening was performed, which led to the identification of several structurally novel inhibitors of the aggregation of the amyloid ß peptide (Aß42). Aggregated Aß42 is a pathological hallmark of Alzheimer's disease and the use of small molecules to inhibit the aggregation process has been identified as a potentially valuable therapeutic strategy for disease treatment. Methylated biaurones were associated with highest levels of potency (the most active compound had an IC50 value of 16 µM), establishing this scaffold as a starting point for inhibitor development.
Asunto(s)
Péptidos beta-Amiloides/química , Biflavonoides/síntesis química , Biflavonoides/farmacología , Fragmentos de Péptidos/química , Agregado de Proteínas/efectos de los fármacos , Biflavonoides/química , Técnicas de Química SintéticaRESUMEN
Type-18 or -23 benzocycloheptadienones are readily prepared by ring-closing olefin metatheses. Adding Br2 to 23 and eliminating HBr gave the bromoolefin 28 using DBU or its isomer iso-28 using DABCO, both with near-perfect regiocontrol. Both 28 and iso-28 underwent Sonogashira, Suzuki, Negishi, and Heck couplings as well as Pd-catalyzed alkoxycarbonylations. Hydrolysis of the resulting α-ketoketals and enolization of the liberated α-diketones delivered a portfolio of hitherto unknown 3,4-benzotropolones. The 8-ethoxycarbonylated dimethyl-3,4-benzotropolone 50 obtained by this route was dimethylated to give goupiolone A (52). This synthesis encompasses 9 steps from 22, that is, half as many as the only previous synthesis (19 steps). A variant of our route afforded the 1,8-dibromide 54. Coupling with excess phenylboronic acid and ketal hydrolysis provided the diphenylated benzotropolone 56 and suggests a strategy, by which the natural bispulvinone aurantricholone (7) might be reached.
Asunto(s)
Biflavonoides/química , Catequina/análogos & derivados , Biflavonoides/síntesis química , Catálisis , Catequina/síntesis química , Catequina/química , Halogenación , Conformación Molecular , Paladio/química , EstereoisomerismoRESUMEN
Although plasmin inhibitors could be used in multiple disorders, their use has been restricted to preventing blood loss in hemostatic dysregulation because of poor efficacy and adverse effects of current agents. We reasoned that a new class of direct inhibitors that offer better efficacy, selectivity, and safety could be discovered by exploiting allosterism in plasmin, a protease homologous to other allosteric serine proteases. We report on the synthesis, biological activity, and mechanism of action of a group of small molecules, called non-saccharide glycosaminoglycan mimetics (NSGMs), as direct allosteric plasmin inhibitors. Our results show that distinct NSGMs selectively inhibit human full-length plasmin. The molecule inhibited clot lysis, alluding to its promise as an allosteric regulator of plasmin. We show that direct allosteric inhibition of plasmin could led to new antifibrinolytic agent(s) that may exhibit better efficacy, potency, selectivity, and safety in comparison to current therapy.
Asunto(s)
Biflavonoides/farmacología , Fibrinolisina/antagonistas & inhibidores , Glicosaminoglicanos/química , Inhibidores de Serina Proteinasa/farmacología , Ésteres del Ácido Sulfúrico/farmacología , Biflavonoides/síntesis química , Dominio Catalítico , Fibrinólisis/efectos de los fármacos , Heparina/química , Humanos , Cinética , Simulación del Acoplamiento Molecular , Imitación Molecular , Protaminas/farmacología , Inhibidores de Serina Proteinasa/síntesis química , Relación Estructura-Actividad , Ésteres del Ácido Sulfúrico/síntesis químicaRESUMEN
In the present study, pear polyphenol oxidase (PPO) was purified, immobilized and applied for the synthesis of theaflavin-3,3'-digallate (TF3). Firstly, PPO of pear (Pyrus bretschneideri Rehd cv. Huangguan) was purified 24.36-fold in specific activity with a recovery of 6.77% by sequential use of precipitation with 70% saturated ammonium sulfate and chromatography of DEAE-Sepharose Fast Flow column. The purified pear PPO, found to be a dimer of identical subunits of molecular mass 35kDa, was then successfully immobilized onto Fe3O4/chitosan nanoparticles via glutaraldehyde coupling reaction. Finally, TF3 was effectively synthesized by applying the immobilized PPO as biocatalyst with epicatechin gallate (ECG) and epigallocatechin-3-O-gallate (EGCG) as substrates, and the maximum yield of TF3 was 42.23% based on the amount of ECG added. In addition, the immobilized enzyme still remained 85% of its initial ability after successive usage of 8 cycles and could be stored for 30days with less loss of activity. All the results suggest that the developed procedure is quite useful and has great potential for synthesis of TF3 and other theaflavins.
Asunto(s)
Biflavonoides/síntesis química , Catequina/análogos & derivados , Catecol Oxidasa/química , Enzimas Inmovilizadas/química , Proteínas de Plantas/química , Biocatálisis , Catequina/síntesis química , Catequina/química , Catecol Oxidasa/aislamiento & purificación , Reactivos de Enlaces Cruzados/química , Enzimas Inmovilizadas/aislamiento & purificación , Equipo Reutilizado , Óxido Ferrosoférrico/química , Glutaral/química , Cinética , Nanopartículas del Metal/química , Proteínas de Plantas/aislamiento & purificación , Multimerización de Proteína , Pyrus/química , Pyrus/enzimología , Especificidad por SustratoRESUMEN
An efficient and versatile synthetic method for labile polyphenols was established using 2-nitrobenzenesulfonate (Ns) as a protecting group for phenol. This methodology provides regio- and stereoselective access to a range of methylated catechins, such as methylated epigallocatechin gallates, that are not readily available from natural sources. In addition, biomimetic synthesis of theaflavins from catechins was accomplished using Ns protection to minimize undesired side reactions of electron-rich aromatic rings during oxidation, enabling construction of the complex benzotropolone core in a single-step oxidative coupling reaction. Availability of these compounds will aid detailed structure-biological activity relationship studies of catechins.
Asunto(s)
Bencenosulfonatos/química , Biflavonoides/síntesis química , Catequina/síntesis química , Polifenoles/síntesis química , Antioxidantes/química , Biflavonoides/química , Catequina/análogos & derivados , Catequina/química , Metilación , Oxidación-Reducción , Relación Estructura-ActividadRESUMEN
The acylation of procyanidin B4 with a saturated fatty acid chloride containing 18 carbon atoms was studied in order to obtain procyanidin B4 3-O-di-stearic acid conjugate. This compound was structurally characterised by mass spectrometry and 1D and 2D NMR techniques. Derivatization of malvidin-3-glucoside using stearoyl chloride in acetonitrile was also performed yielding mono-, di- and tri-stearic ester derivatives. The novel derivatives obtained revealed significant antioxidant activity, although lower than the respective precursors. However, the chemical modification of anthocyanins and procyanidins (water soluble pigments) to more lipophilic compounds has the advantage of increased bioavailability in biological matrices, and to potentiate their application in food matrices and cosmetic products.
Asunto(s)
Antocianinas/química , Antioxidantes/química , Biflavonoides/química , Catequina/química , Glucósidos/química , Proantocianidinas/química , Ácidos Esteáricos/química , Antocianinas/síntesis química , Biflavonoides/síntesis química , Catequina/síntesis química , Glucósidos/síntesis química , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Proantocianidinas/síntesis químicaRESUMEN
Seven new O-methylated theaflavins (TFs) were synthesized by using O-methyltransferase from an edible mushroom. Using TFs and O-methylated TFs, metabolic stability in pooled human liver S9 fractions and inhibitory effect on H(2)O(2)-induced oxidative damage in human HepG2 cells were investigated. In O-methylation of theaflavin 3'-O-gallate (TF3'G), metabolic stability was potentiated by an increase in the number of introduced methyl groups. O-methylation of TF3,3'G did not affect metabolic stability, which was likely because of a remaining 3-O-galloyl group. The inhibitory effect on oxidative damage was assessed by measuring the viability of H(2)O(2)-damaged HepG2 cells treated with TFs and O-methylated TFs. TF3,3'G and O-methylated TFs increased cell viabilities significantly compared with DMSO, which was the compound vehicle (p < 0.05), and improved to approximately 100%. Only TF3'G did not significantly increase cell viability. It was suggested that the inhibitory effect on H(2)O(2)-induced oxidative damage was potentiated by O-methylation or O-galloylation of TFs.
Asunto(s)
Biflavonoides/química , Biflavonoides/farmacología , Catequina/química , Catequina/farmacología , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Oxígeno/química , Biflavonoides/síntesis química , Biflavonoides/metabolismo , Catequina/síntesis química , Catequina/metabolismo , Estabilidad de Medicamentos , Células Hep G2 , Humanos , MetilaciónRESUMEN
The first stereoselective syntheses of doubly linked (A-type) oligocatechins, (+)-procyanidinâ A2 and (+)-cinnamtanninâ B1, have been achieved. Ethylenedioxy-bridged flavans served as excellent platforms, thus allowing annulation with nucleophilic catechin units in a stereoselective manner. An additional key was the new synthetic approach to selectively protected nucleophilic catechin, thus enabling regioselective construction of the key dioxabicyclo skeleton of the A-type oligocatechins.
Asunto(s)
Biflavonoides/síntesis química , Catequina/química , Proantocianidinas/síntesis química , Biflavonoides/química , Catequina/síntesis química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Proantocianidinas/química , EstereoisomerismoRESUMEN
Proanthocyanidins, also known as condensed tannins and/or oligomeric flavonoids, occur in many edible plants and have various interesting biological activities. Previously, we reported a synthetic method for the preparation of various procyanidins in pure form and described their biological activities. Here, we describe the synthesis of procyanidin B1 acetylated analogs and discuss their inhibition activities against HeLa S3 cell proliferation. Surprisingly, the lower-unit acetylated procyanidin B1 strongly inhibited the proliferation of HeLa S3 cells. This molecule showed much stronger inhibitory activity than did epigallocatechin-3-O-gallate (EGCG), green tea polyphenol, and dimeric compounds that included EGCG as a unit. This result suggests that the phenolic hydroxyl groups of the upper-units in flavan-3-ols are important for their inhibitory activity against cancer cell proliferation and that a hydrophobic lower unit dimer enhances this activity.