Bioavailability of black tea theaflavins: absorption, metabolism, and colonic catabolism

Data obtained with in vitro fecal incubations and a feeding study indicate black tea theaflavin and its galloyl derivatives are not absorbed in detectable amounts in either the upper or lower gastrointestinal tract. The theaflavin skeleton is comparatively resistant to degradation by colonic bacteria with a 67% recovery being obtained after a 24 h incubation, which yielded 21 phenolic and aromatic catabolites. The theaflavin galloyl moiety was removed by the microbiota, and the released gallic acid further transformed to 3-O- and 4-O-methyl gallic acids, pyrogallol-1-sulfate and pyrogallol-2-sulfate, which were excreted in urine in amounts equivalent to 94% of intake. The main urinary product potentially derived from breakdown of the theaflavin skeleton was 3-(4′-hydroxyphenyl)propionic acid. A number of the colonic catabolites originating from gallic acid and theaflavins has been reported to be bioactive in ex vivo and in vitro models with a variety of potential modes of action

Exploring the Remote Reactivity of π-Extended Carbonyl Compounds: the Vinylogous Alkylidene Malononitrile Activation Strategy

The development of enabling chemical transformations which exploit highly functionalized polydentate substrates – e.g. π-extended carbonyl compounds – with maximum efficiency and chemo-, regio-, and stereocontrol is a main challenge at the forefront of organic synthesis. To this end, merging the vinylogy concept with the malononitrile activation strategy, and the chiral iminium ion LUMO-lowering catalysis turned out to be a successful option, and several achievements were recently obtained on the exploitation of these concepts in asymmetric synthesis. We herein emphasize the role of the malononitrile handle as a crucial (and optionally traceless) ingredient enabling the selective activation of polyunsaturated carbonyl pro- nucleophiles. In particular, the synthetic potential of previously uncharted vinylogous alkylidene malononitriles I-III is highlighted, together with the modalities by which the efficient and chemo-, regio-, diastereo-, and enantioselective synthesis of collections of valuable carbocyclic and heterocyclic compounds were realized

Exploiting the Distal Reactivity of Indolyl- methylenemalononitriles: an Asymmetric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly of Elusive Dihydrocarbazoles

An unprecedented modality for in situ generation of indole-ortho-quinodimethanes from 2-methylindole-based methylenemalononitriles by amine-mediated remote C(sp³)-H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole-3-carboxyaldehyde structures via formal asymmetric [4+2] eliminative cycloaddition governed by α,α-diphenylprolinol trimethylsilyl ether catalyst

Catalytic, Enantioselective Vinylogous Mukaiyama Aldol Reaction of Furan-Based Dienoxy Silanes: A Chemodivergent Approach to γ-Valerolactone Flavan-3-ol Metabolites and δ-Lactone Analogues

The asymmetric synthesis of a set of hydroxyphenyl γ-valerolactones was achieved starting from 2-silyloxyfuran and alkoxy-substituted benzaldehydes as common precursors. Key synthesis steps included an enantioselective vinylogous Mukaiyama aldol reaction and a Barton–McCombie deoxygenation. Five enantioenriched γ-valerolactone targets were obtained in 5–6 steps, 18–63% overall yields and 82–98 % ee, paving the way for the straightforward entry to this class of biologically effective and poorly available flavan-3-ol metabolites. In parallel, an unprecedented one-pot reductive ring expansion process was fortuitously discovered, yielding racemic δ-lactone analogues from phenolic butanolide precursors

5-(3′,4′-Dihydroxyphenyl)-γ-valerolactone and its sulphate conjugates, representative circulating metabolites of flavan-3-ols, exhibit anti-adhesive activity against uropathogenic Escherichia coli in bladder epithelial cells

Urinary tract infections (UTI) are mostly caused by uropathogenic Escherichia coli (UPEC). Cranberry-based products have shown preventive effects against UTI, and this has been partially attributed to their A-type proanthocyanidin content. However, recent evidence reports phenyl-γ-valerolactones as the most relevant urinary metabolites of cranberry procyanidins, and candidates these compounds as plausible responsible for the protective effects of cranberries against UTI. This paper studied the inhibition of the adherence of UPEC ATCC®53503™ to T24 bladder epithelial cells by physiological concentrations of differently sulphated dihydroxyphenyl-γ-valerolactones. Moreover, the transformations of these molecules in the cell media were evaluated by UHPLC-MSn. All dihydroxyphenyl-γ-valerolactone derivatives showed anti-adhesive activity at 100 μM, while 5-(3′-hydroxyphenyl)-γ-valerolactone-4-O-sulphate also showed neuro-protective effects at 50 μM. Some compounds underwent extensive metabolism during cell incubation, mainly deconjugation of sulphate moieties and opening of the lactone ring. These results shed light on the flavan-3-ol metabolites behind the prophylactic effect of cranberries against UTI

Pushing the boundaries of vinylogous reactivity: catalytic enantioselective mukaiyama aldol reactions of highly unsaturated 2-silyloxyindoles

The first example of catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2-silyloxyindoles is reported. The reaction utilizes a chiral Lewis base-catalyzed Lewis acid-mediated technology to deliver homoallylic 3-polyenylidene 2-oxindoles with extraordinary levels of regio-, enantio-, and geometrical selectivity. This work highlights a subtle yet decisive influence of the indole N-substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the 13C NMR chemical shifts of the C-ω remote site within homologous silyloxyindole donors enabled rationalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor

Synthetic and analytical strategies for the quantification of phenyl-γ-valerolactone conjugated metabolites in human urine

Scope: The contribution of the gut microbiota to the metabolism of catechins and proanthocyanidins remains unclear. Phenyl-γ-valerolactones have been identified as the most representative metabolites of these dietary flavan-3-ols, but their accurate quantification has posed problems because of a lack of appropriate bioanalytical standards. This work aimed at synthesizing a novel set of sulphate- and glucuronide-conjugated phenyl-γ-valerolactones and at developing an analytical platform using UHPLC-ESI-MS/MS for their quantification in urine. Methods and results: Eight glucuronide and sulphate conjugates of hydroxyphenyl-γ-valerolactones were synthesized and used as analytical standards, together with five phenyl-γ-valerolactone aglycones, for the development of a high-throughput, validated analytical method. Chromatographic and MS conditions were optimized. The method validation showed acceptable linearity, intra-day and inter-day repeatability, and accuracy, with the analytical range, limit of detection (LOD), and lower limit of quantification (LLOQ) varying notably among compounds. The method was used to calculate the excretion of phenyl-γ-valerolactones in healthy subject consuming green tea, providing novel information on the real concentrations of phenyl-γ-valerolactones in urine. Conclusion: This work opens the door to better studying the bioavailability of flavan-3-ols and the real exposition to flavan-3-ol sources, as well as to define the bioactivity of these colonic metabolites in cell assays

Phenyl-gamma-valerolactones, flavan-3-ol colonic metabolites, protect brown adipocytes from oxidative stress without affecting their differentiation or function

Scope: Consumption of products rich in flavan-3-ols, such as tea and cocoa, has been associated with decreased obesity, partially dependent on their capacity to enhance energy expenditure. Despite these phenolics having been reported to increase the thermogenic program in brown and white adipose tissue, flavan-3-ols are vastly metabolised in vivo to phenyl-γ-valerolactones. Therefore, we hypothesize that phenyl-γ-valerolactones may directly stimulate the differentiation and the activation of brown adipocytes. Methods and results: Immortalized brown pre-adipocytes were differentiated in presence of (R)-5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (VL1), (R)-5-(3'-hydroxyphenyl)-γ-valerolactone-4′-O-sulphate (VL2), (R)-5-phenyl-γ-valerolactone-3',4'-di-O-sulphate (VL3), at concentrations of 2 or 10μM, whereas fully differentiated brown adipocyte were treated acutely (6-24h). None of the treatments regulated the expression levels of the uncouple protein 1, nor of the main transcription factors involved in brown adipogenesis. Similarly, mitochondrial content was unchanged after treatments. Moreover these compounds did not display peroxisome proliferator-activated receptor γ-agonist activity, as evaluated by luciferase assay, and did not enhance norepinephrine-stimulated lipolysis in mature adipocytes. However, both VL1 and VL2 prevented oxidative stress caused by H2O2. Conclusion: Phenyl-γ-valerolactones and their sulphated forms do not influence brown adipocyte development or function at physiological or supraphysiological doses in vitro, but they are active protecting brown adipocytes from increased reactive oxygen species production

Organocatalytic, asymmetric eliminative [4+2] cycloaddition of allylidene malononitriles with enals: rapid entry to cyclohexadiene-embedding linear and angular polycycles

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated

Bioavailability of Black Tea Theaflavins: Absorption, Metabolism, and Colonic Catabolism

Data obtained with in vitro fecal incubations and a feeding study indicate black tea theaflavin and its galloyl derivatives are not absorbed in detectable amounts in either the upper or lower gastrointestinal tract. The theaflavin skeleton is comparatively resistant to degradation by colonic bacteria with a 67% recovery being obtained after a 24 h incubation, which yielded 21 phenolic and aromatic catabolites. The theaflavin galloyl moiety was removed by the microbiota, and the released gallic acid further transformed to 3-<i>O</i>- and 4-<i>O</i>-methyl gallic acids, pyrogallol-1-sulfate and pyrogallol-2-sulfate, which were excreted in urine in amounts equivalent to 94% of intake. The main urinary product potentially derived from breakdown of the theaflavin skeleton was 3-(4′-hydroxyphenyl)­propionic acid. A number of the colonic catabolites originating from gallic acid and theaflavins has been reported to be bioactive in ex vivo and in vitro models with a variety of potential modes of action