Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

<p>Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation that can generate bio-inactive or toxic metabolites. As an example, the cough suppressant dextromethorphan undergoes such a P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan. This metabolite antagonizes the NMDA receptor causing hallucinations, which encourages recreational abuse. To circumvent this undesired metabolism, we have designed, synthesized, and evaluated <i>in vitro </i>and <i>in vivo</i> new fluoroalkyl analogs of dextromethorphan that display improved pharmacokinetic profiles relative to dextromethorphan and related analogs currently in clinical trials. Specifically, the fluorinated analogs minimized metabolic degradation and increased CNS exposure relative to DXM <i>in vivo</i>. Ultimately, these fluorinated motifs might be applicable to other aryl-methyl ether containing compounds as a strategy to improve pharmacokinetic profiles.<b></b></p>

Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability

<p>Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation that can generate bio-inactive or toxic metabolites. As an example, the cough suppressant dextromethorphan undergoes such a P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan. This metabolite antagonizes the NMDA receptor causing hallucinations, which encourages recreational abuse. To circumvent this undesired metabolism, we have designed, synthesized, and evaluated <i>in vitro </i>and <i>in vivo</i> new fluoroalkyl analogs of dextromethorphan that display improved pharmacokinetic profiles relative to dextromethorphan and related analogs currently in clinical trials. Specifically, the fluorinated analogs minimized metabolic degradation and increased CNS exposure relative to DXM <i>in vivo</i>. Ultimately, these fluorinated motifs might be applicable to other aryl-methyl ether containing compounds as a strategy to improve pharmacokinetic profiles.<b></b></p>

Changes in defense-related enzymes and phenolics in resistant and susceptible common wheat cultivars under aphid stress

The cereal aphids Rhopalosiphum padi L. are serious pests on grain crops, reducing the quality and yield by direct feeding damage and virus transmission. The changes in the physiological and biochemical parameters of two wheat cultivars under aphid stress were investigated to understand aphid-resistance mechanisms. The activity levels of phenylalanine ammonia-lyase (PAL), peroxidase (POD), tyrosine ammonia-lyase (TAL), Ca2+-ATPase and Mg2+-ATPase in resistant cultivar W0923 increased during aphid feeding, and most of them were significantly higher than those in the susceptible cultivar GN21. However, these enzyme activities increased and then decreased in GN21. The polyphenol oxidase (PPO) activity in W0923 was maintained longer than in GN21. The total phenol contents of the two cultivars exhibited significant increases on the 15th day compared with the untreated controls, and the content in W0923 was significantly higher than in GN21 by the 30th day. Most of the POD, PPO, PAL, TAL and Ca2+-ATPase activities and phenolic metabolite contents were higher in W0923 than in GN21 under the untreated control conditions. The Ca2+-ATPase and PAL activities positively correlated with POD, PPO and Mg2+-ATPase activities. Ca2+-ATPase and PAL may be key biochemical markers for evaluating aphid resistance. W0923 had a strong ability to maintain higher enzyme activities and synthesize more phenols and tannins than GN21, which contributed to aphid resistance.

The gut microbiome drives inter- and intra-individual differences in metabolism of bioactive small molecules

The origin of inter-individual variability in the action of bioactive small molecules from the diet is poorly understood and poses a substantial obstacle to harnessing their potential for attenuating disease risk. Epidemiological studies show that coffee lowers the risk of developing type 2 diabetes, independently of caffeine, but since coffee is a complex matrix, consumption gives rise to different classes of metabolites in vivo which in turn can affect multiple related pathways in disease development. We quantified key urinary coffee phenolic acid metabolites repeated three times in 36 volunteers, and observed the highest inter- and intra-individual variation for metabolites produced by the colonic microbiome. Notably, a urinary phenolic metabolite not requiring the action of the microbiota was positively correlated with fasting plasma insulin. These data highlight the role of the gut microbiota as the main driver of both intra- and inter-individual variation in metabolism of dietary bioactive small molecules.

The Impact of Polyphenol on General Nutrient Metabolism in the Monogastric Gastrointestinal Tract

Polyphenols are bioactive compounds occurring in plant foods, which are considered significant owing to their contribution to human health and the prevention of chronic diseases. Phenolic compounds mainly depend on plant food structure and the interaction with other food constituents, mostly proteins, lipids, and carbohydrates. The interaction with the food matrices can obstruct or enhance nutrient accessibility and availability and even impair others. Food digestion is a complex process where ingested foods are converted to nutrients via mechanical and enzymatic alterations. The absorption of nutrients predominantly occurs in the small and large intestine, respectively. The metabolised product, however, is the main bioactive component due to their ability to enter the systemic circulation and reach the targeted organs. There is limited knowledge on the cellular uptake, phenolic metabolite, and polyphenolic effect in the gastrointestinal ecosystem. Therefore, improved understanding of the biological properties and stages of dietary phenols is essential for the effective utilization of their therapeutic potentials. This review will explore, summarise, and collate current information on how polyphenols influence nutrient metabolism, bioavailability, and the biotransformation stages.

Increase of 4-Hydroxybenzoic, a Bioactive Phenolic Compound, after an Organic Intervention Diet

Consumption of organic products is increasing yearly due to perceived health-promoting qualities. Several studies have shown higher amounts of phytochemicals such as polyphenols and carotenoids in foods produced by this type of agriculture than in conventional foods, but whether this increase has an impact on humans still needs to be assessed. A randomized, controlled and crossover study was carried out in nineteen healthy subjects aged 18–40 years, who all followed an organic and conventional healthy diet, both for a 4-week period. Analysis of biological samples revealed a significant increase on the excretion of 4-hydroxybenzoic acid (4-HBA), a phenolic metabolite with biological activity, after the organic intervention. However, no changes were observed in the other variables analyzed.

Hydroquinone-Derivatives Induce Cell Death in Chronic Myelogenous Leukemia

Hydroquinone (HQ) is a phenolic metabolite of benzene, which is used as a skin whitener. Insects synthesize this natural compound as a deterrent and mushrooms as a toxin. Pro-apoptotic effects of HQ were previously documented on various cancer cell types. Here we investigated the cell-death inducing mechanisms of this compound in chronic myeloid leukemia cell models.

Anti-platelet and anti-thrombogenic effects of shikimic acid in sedentary population

Thisex vivostudy was performed to evaluate the anti-platelet and anti-thrombogenic potential of shikimic acid (SA), a plant phenolic metabolite.

The ex vivo antiplatelet activation potential of fruit phenolic metabolite hippuric acid

Active metabolite of polyphenol intake, hippuric acid, reduces platelet activation-related conformational change and de-granulationex vivothereby alleviating thrombogenesis.