RESUMEN
A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(I)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(I)-catalyzed process has been used to produce more than 1500 kg of idasanutlin. The manufacturing process will be described, highlighting the exceptionally selective and consistent cycloaddition/isomerization/hydrolysis sequence. The excellent yields, short cycle times and reduction in waste streams result in a sustainable production process with low environmental impact.
Asunto(s)
Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirrolidinas/síntesis química , para-Aminobenzoatos/síntesis química , Catálisis , Cobre , Reacción de Cicloadición , Hidrólisis , IsomerismoRESUMEN
Chlorogenic acids (CGA) are found in many plant-derived foodstuffs and are claimed to have various beneficial effects on human health. Potatoes are a major component of the human diet and contain CGA, but little is known about their abundance in these important tubers. We therefore used a rapid, sensitive, and selective method for quantifying CGAs in food using ultra-high performance LC diode array detection (UHPLC-DAD). We also established an optimized sample preparation protocol based on ultrafiltration and used these techniques to quantify the CGA contents of selected potato varieties (fresh and after storage) and potato products. The measured CGA concentrations in potato skins were 37-636 mg/100 g dry weight (DW) and were three to four times greater than those in the flesh. Storage reduced the CGA levels in potatoes by up to 81%. The studied potato purees contained 4-11 mg CGA/100 g DW. In addition, the quinic acid contents of potato flesh (11-95 mg/100 g DW) and puree (11-22 mg/100 g DW) were measured using stable isotope dilution analysis. None of the tested samples contained caffeic acid. Overall, our results demonstrated that the UHPLC-DAD method can be used to rapidly quantify CGA levels in potatoes and related food products.
Asunto(s)
Ácido Clorogénico/análisis , Cromatografía Líquida de Alta Presión/métodos , Solanum tuberosum/químicaRESUMEN
BACKGROUND: Bilberries (Vaccinium myrtillus L.) have been suggested to have preventive properties against diseases associated with oxidative stress such as colon cancer or inflammatory bowel diseases. Therefore the gastrointestinal tract is regarded as a potential target for prevention. In this study the antioxidative properties of a commercially available anthocyanin-rich bilberry extract (BE) were investigated in comparison with four different BE-loaded microcapsule systems. As markers to describe the antioxidant status in this cellular system, intracellular reactive oxygen species (ROS) levels, oxidative DNA damage and total glutathione (tGSH) levels were monitored. RESULTS: Incubations with the BE-loaded capsule systems showed an increase in cellular glutathione levels and reduction of ROS levels at high BE concentrations (100-500 µg mL(-1) ) and a positive effect on the formation of DNA strand breaks (5-10 µg mL(-1) BE). The biological properties of BE-loaded pectin amide core-shell capsules, whey protein matrix capsules and coated apple pectin matrix capsules were comparable to those of the non-encapsulated BE. CONCLUSION: Overall, the BE and the encapsulated BE types tested have antioxidative activity under the studied assay conditions in terms of the prevention of oxidative DNA damage, the reduction of intracellular ROS and the enhancement of cellular tGSH.
Asunto(s)
Antocianinas/administración & dosificación , Antioxidantes/administración & dosificación , Frutas/química , Estrés Oxidativo/efectos de los fármacos , Vaccinium myrtillus/química , Antocianinas/farmacología , Antioxidantes/farmacología , Células CACO-2 , Cápsulas/química , Daño del ADN/efectos de los fármacos , Glutatión/metabolismo , Humanos , Malus , Proteínas de la Leche , Pectinas , Extractos Vegetales , Especies Reactivas de Oxígeno/metabolismo , Proteína de Suero de LecheRESUMEN
UNLABELLED: In the present study the anthocyanin content of commercially available bilberry juices and fresh fruits were quantified by using 15 authentic anthocyanin standards via high performance liquid chromatography with an ultra-violet detector (HPLC-UV/VIS). Delphinidin-3-O-glucopyranoside, delphinidin-3-O-galactopyranoside, and cyanidin-3-O-arabinopyranoside were the major anthocyanins found in juices, nectar, and fresh bilberries. In contrast, fresh blueberries had higher concentrations of malvidin-3-O-arabinopyranoside and petunidin-3-O-galactopyranoside. Up to 438 mg anthocyanins per 100 g fresh weight (2762 mg/100 g dry weight (DW)) were detected in blueberries from various sources, whereas bilberries contained a maximum of 1017 mg anthocyanins per 100 g fresh weight (7465 mg/100 g DW). Commercially available bilberry and blueberry juices (n= 9) as well as nectars (n= 4) were also analyzed. Anthocyanin concentrations of juices (1610 mg/L to 5963 mg/L) and nectar from bilberries (656 mg/L to 1529 mg/L) were higher than those of blueberry juices (417 mg/L) and nectar (258 mg/L to 386 mg/L). We conclude that using several authentic anthocyanin references to quantify anthocyanin contents indicated them to be up to 53% and 64% higher in fresh bilberries and blueberries, respectively, than previously reported using cyanidin-3-O-glucoside. This study has also demonstrated that commercially available juices produced from bilberries contain much higher anthocyanin concentrations than those from blueberries. PRACTICAL APPLICATION: We have investigated the contents of a special class of antioxidants, namely anthocyanins in blueberry and billberry fruits and juices commercially available in Germany. To achieve reliable data we have used authentic standards for the first time. We think that our results are important in the field of nutritional intake of this important class of polyphenols and fruit juice companies get a closer insight in the occurrence of these antioxidants in market samples to be used in food composition databases and for nutritional survey.
Asunto(s)
Antocianinas/análisis , Antioxidantes/análisis , Bebidas/análisis , Arándanos Azules (Planta)/química , Frutas/química , Vaccinium myrtillus/química , Cromatografía Líquida de Alta Presión , Manipulación de Alimentos , Alimentos Funcionales , Alemania , Glicósidos/análisis , Concentración de Iones de Hidrógeno , Especificidad de la Especie , EspectrofotometríaRESUMEN
Bilberries (Vaccinium myrtillus L.) and their major polyphenolic constituents, anthocyanins, have preventive activities inter alia against colon cancer and inflammatory bowel diseases. However, anthocyanins are sensitive to environmental conditions; thus their bioavailability in the gastrointestinal tract is an important determinant of their in vivo activity. In the study reported here, the potential benefits of encapsulating an anthocyanin rich bilberry extract (BE) on anthocyanin stability were investigated. Nonencapsulated BE and three different BE loaded microcapsule systems were incubated in simulated gastric fluid (SGF) and fed state simulated intestinal fluid (FeSSIF). After exposure to these media, released anthocyanins were identified and quantified by HPLC with UV/Vis detection. Although a rapid release of anthocyanins was observed within the first 20 min, encapsulation of anthocyanins doubled the amount of available anthocyanins after 150 min of incubation. These results illustrate the ability of encapsulation to inhibit early degradation of anthocyanins in the intestinal system.
Asunto(s)
Antocianinas/farmacocinética , Composición de Medicamentos/métodos , Vaccinium myrtillus/química , Química Farmacéutica , Estabilidad de Medicamentos , Humanos , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Cinética , Modelos Biológicos , Extractos VegetalesRESUMEN
Numerous studies have shown that green tea polyphenols can be degraded in the colon, and there is abundant knowledge about the metabolites of these substances that appear in urine and plasma after green tea ingestion. However, there is very little information on the extent and nature of intestinal degradation of green tea catechins in humans. Therefore, the aim of this study was to examine in detail the microbial metabolism and chemical stability of these polyphenols in the small intestine using a well-established ex vivo model. For this purpose, fresh ileostomy fluids from two probands were incubated for 24 h under anaerobic conditions with (+)-catechin (C), (-)-epicatechin (EC), (-)-epicatechin 3-O-gallate (ECG), (-)-epigallocatechin (EGC), (-)-epigallocatchin 3-O-gallate (EGCG) and gallic acid (GA). After lyophilisation and extraction, metabolites were separated, identified and quantified by high performance liquid chromatography-photodiode array detection (HPLC-DAD) and HPLC-ESI-tandem mass spectrometry. Two metabolites of EC and C (3', 4', 5'-trihydroxyphenyl-γ-valerolactone and 3', 4'-dihydroxyphenyl-γ-valerolactone) were identified. In addition, 3', 4', 5'-trihydroxyphenyl-γ-valerolactone was detected as a metabolite of EGC, and (after 24-h incubation) pyrogallol as a degradation product of GA. Cleavage of the GA esters of EGCG and ECG was also observed, with variations dependent on the sources (probands) of the ileal fluids, which differed substantially microbiotically. The results provide new information about the degradation of green tea catechins in the gastrointestinal tract, notably that microbiota-dependent liberation of GA esters may occur before these compounds reach the colon.