Hagen Schroeter

Mars, Inc., Маклин, Virginia, United States

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Publications (48)268.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: An understanding of the pharmacokinetics of structurally related (-)-epicatechin metabolites (SREM) is a prerequisite for considering cocoa flavanols (CF) in the context of dietary recommendations. The objective of this study was to compare the absorption, metabolism, and excretion of SREM in healthy young and elderly Caucasian men. Intra-individual variability of SREM was assessed in 7 young subjects, after consuming 10.7 mg CF/kg body weight (BW) on two occasions separated by one week. The effect of age on flavanols ADME was assessed in 20 young (18-35y) and 20 elderly (65-80y) healthy male subjects receiving 5.3 and 10.7 mg total CF/kg BW or 1 g of acetaminophen as a control to compare differences in Phase II metabolism on 3 days separated by 1 week of wash-out. Blood and urine samples were collected for 24 h post consumption. The intra-individual variation, measured as CV(%) with respect to the area-under-the-curve of the concentration over time (AUC(0-6h) ) of SREM, was 16%, whilst the inter-individual variation in AUC(0-6h) , was 38%, comparable to acetaminophen (39%). The AUC(0-6h) and the 24 h excretion of total SREM was not significantly different between young and elderly subjects. At the high intake amount, the AUC(0-6h) of (-)-epicatechin-3'-β-D-glucuronide was greater in elderly subjects, whereas the AUC(0-6h) of 3'-O-methyl-(-)-epicatechin-5-sulfate and 3'-O-methyl-(-)-epicatechin-7-sulfate as well as the 24 h urinary excretion of γ-valerolactone (γ-VL) metabolites were lower in the elderly. Cocoa flavanols are absorbed, metabolized, and excreted in healthy young and elderly subjects with relatively small differences between the two groups. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Molecular Nutrition & Food Research 05/2015; DOI:10.1002/mnfr.201500091 · 4.91 Impact Factor
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    ABSTRACT: The first novel stereoselective synthesis of naturally occurring A1 (1) and A2 proanthocyanidins (2) has been achieved. The key synthetic steps involved (a) the formation of a coupled product (13 or 14) between an open chain C-ring C-4 hydroxyethoxy analogue of either (+)-catechin or (-)-epicatechin with 5,7,3',3'-tetra-O-benzyl-(+)-catechin/-(-)-epicatechin in the presence of bentonite clay K-10, (b) removal of benzyl protecting groups under mild catalytic hydrogenation conditions to form the desired A-type compound in situ as a mixture of diastereomers via ketal/oxonium ion/carbonium ion formation, and (c) separation of the diasteromers via silica gel column chromatography. The structures of A1 and A2 proanthocyanidins were unequivocally established by analytical comparison to the natural products. Following this methodology, an additional six diastereomers of proanthocyanidins A1 and A2 have been synthesized. A plausible mechanism for the formation of the A-type linkage in proanthocyanidins has been proposed.
    Organic Letters 04/2015; 17(10). DOI:10.1021/acs.orglett.5b00646 · 6.32 Impact Factor
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    ABSTRACT: Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. To investigate associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). Data was available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan-3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Median intake of total flavan-3-ols was 1034mg/d (range: 0-8531mg/d) for men and 970mg/d (0-6695mg/d) for women, median intake of flavan-3-ol monomers was 233mg/d (0-3248mg/d) for men and 217 (0-2712mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow up, there were 8463 cardio-vascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI: 0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 03/2015; 31. DOI:10.1016/j.freeradbiomed.2015.03.005 · 5.71 Impact Factor
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    ABSTRACT: Dietary interventions with flavan-3-ols have shown beneficial effects on vascular function. The translation of these findings into the context of the health of the general public requires detailed information on habitual dietary intake. However, only limited data are currently available for European populations. Therefore, in the present study, we assessed the habitual intake of flavan-3-ol monomers, proanthocyanidins (PA) and theaflavins in the European Union (EU) and determined their main food sources using the EFSA (European Food Safety Authority) Comprehensive European Food Consumption Database. Data for adults aged 18-64 years were available from fourteen European countries, and intake was determined using the FLAVIOLA Flavanol Food Composition Database, developed for the present study and based on the latest US Department of Agriculture and Phenol-Explorer databases. The mean habitual intake of flavan-3-ol monomers, theaflavins and PA ranged from 181 mg/d (Czech Republic) to 793 mg/d (Ireland). The highest intakes of flavan-3-ol monomers and theaflavins were observed in Ireland (191/505 mg/d) and the lowest intakes in Spain (24/9 mg/d). In contrast, the daily intake of PA was highest in Spain (175 mg/d) and lowest in The Netherlands (96 mg/d). Main sources were tea (62 %), pome fruits (11 %), berries (3 %) and cocoa products (3 %). Tea was the major single contributor to monomer intake (75 %), followed by pome fruits (6 %). Pome fruits were also the main source of PA (28 %). The present study provides important data on the population-based intake of flavanols in the EU and demonstrates that dietary intake amounts for flavan-3-ol monomers, PA and theaflavins vary significantly across European countries. The average habitual intake of flavan-3-ols is considerably below the amounts used in most dietary intervention studies.
    The British journal of nutrition 12/2013; DOI:10.1017/S0007114513003930 · 3.34 Impact Factor
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    ABSTRACT: Current evidence suggests that regenerative v. degenerative endothelial responses can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity. We have previously shown that a cocoa flavanol (CF) intervention can improve endothelial function and increase the regenerative capacity of the endothelium by mobilising circulating angiogenic cells in patients with coronary artery disease (CAD). The aim of the present study was to investigate whether CF can lower the levels of circulating endothelial microparticles (EMP), markers of endothelial integrity, along with improvements in endothelial function. The levels of EMP in the frozen plasma samples of CAD patients were measured along with endothelial function (flow-mediated vasodilation, FMD); n 16, FMD data published previously), and these data were compared with those of young (n 12) and age-matched (n 12) healthy control subjects. The CAD patients exhibited significantly increased levels of EMP along with impaired FMD when compared with the healthy control subjects. The levels of CD144+ and CD31+/41- EMP were inversely correlated with FMD (r - 0·67, P= 0·01 and r - 0·59, P= 0·01, respectively). In these CAD patients, the levels of EMP were measured after they had consumed a drink containing 375 mg of CF (high-CF intervention, HiFI) or 9 mg of CF (macro- and micronutrient-matched low-CF control, LoFl) twice daily over a 30-d period in a randomised, double-blind, cross-over study. After 1 month of HiFI, the levels of CD31+/41- and CD144+ EMP decreased ( - 25 and - 23 %, respectively), but not after LoFl. Our data show that flavanols lower the levels of EMP along with higher endothelial function, lending evidence to the novel concept that flavanols may improve endothelial integrity.
    The British journal of nutrition 11/2013; 111(07):1-8. DOI:10.1017/S0007114513003693 · 3.34 Impact Factor
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    ABSTRACT: The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date.
    Bioorganic & medicinal chemistry letters 07/2013; 23(17). DOI:10.1016/j.bmcl.2013.06.092 · 2.33 Impact Factor
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    ABSTRACT: Ten orthogonally protected (−)-epicatechin and 3′- or 4′-O-methyl-(−)-epicatechin derivatives were prepared in a regiospecific and enantioselective manner. For each orthogonally protected (−)-epicatechin derivative, one specific phenolic hydroxyl was protected with a methoxymethyl (MOM) or p-methoxybenyzl (PMB) group and the remainder were protected as benzyl ethers. These uniquely protected (−)-epicatechin derivatives were designed to facilitate the regiospecific installation of a glucuronic acid or sulfate unit onto (−)-epicatechin after selective removal of the MOM or PMB protecting group to provide authentic standards of (−)-epicatechin glucuronides and sulfates.
    Tetrahedron Asymmetry 04/2013; 24(7):362–373. DOI:10.1016/j.tetasy.2013.02.012 · 2.17 Impact Factor
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    ABSTRACT: Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.
    Journal of Medicinal Chemistry 03/2013; 56(6). DOI:10.1021/jm400014c · 5.48 Impact Factor
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    ABSTRACT: Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.
    Bioorganic & medicinal chemistry letters 02/2013; 23(7). DOI:10.1016/j.bmcl.2013.02.024 · 2.33 Impact Factor
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    ABSTRACT: The monoglucuronides and sulfates of epicatechin, 3'-O-methylepicatechin, and 4'-O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans.
    Journal of Natural Products 01/2013; 76(2). DOI:10.1021/np300568m · 3.95 Impact Factor
  • Free Radical Biology and Medicine 11/2012; 53:S183. DOI:10.1016/j.freeradbiomed.2012.10.505 · 5.71 Impact Factor
  • Free Radical Biology and Medicine 11/2012; 53:S129-S130. DOI:10.1016/j.freeradbiomed.2012.10.324 · 5.71 Impact Factor
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    ABSTRACT: A versatile new approach is reported for the total synthesis of five glucuronide metabolites of epicatechin, using selective protection/deprotection techniques.
    Tetrahedron Letters 03/2012; 53(12):1501–1503. DOI:10.1016/j.tetlet.2012.01.054 · 2.39 Impact Factor
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    ABSTRACT: Accumulating data show a causal role for flavanols in the mediation of cardiovascular benefits associated with the consumption of flavanol- and procyanidin-containing foods. Evidence for a direct causal role for procyanidins in this context is far less profound due to the poor absorption of procyanidins. However, it has been proposed that procyanidins may break down in the gastrointestinal tract, resulting in monomeric flavanols, which contribute to the systemic flavanol pool. Verification or rejection of this supposition could significantly affect the interpretation of epidemiologic and dietary intervention data and the design of food-content databases. We assessed the respective contribution of flavanols and procyanidins to the systemic pool of flavanols and 5-(3,4-dihydroxyphenyl)-γ-valerolactone (γ-VL) in humans. Test drinks that contained only flavanols (D1), procyanidins with a degree of polymerization that ranged from 2 to 10 (D2-10), or flavanols and procyanidins with a degree of polymerization that ranged from 2 to 10 (D1-10) were consumed by subjects (n = 12) according to a randomized, double-masked, crossover design. Plasma and urine samples were collected postprandially and analyzed. The ingestion of D1-10 resulted in the systemic presence of flavanols (plasma concentration: 863 ± 77 nmol/L), γ-VLs (24-h urine: 93 ± 18 μmol), and minute concentrations of procyanidin B2. With correction for small residual amounts of flavanols present in D2-10, only negligible concentrations of circulating flavanols were detected after ingestion of the drink, whereas the intake of D1 resulted in circulating flavanol concentrations similar to those detected after D1-10 consumption. These outcomes show that dietary procyanidins do not contribute to the systemic pool of flavanols in humans. Thus, these data reject the notion that procyanidins, through their breakdown into flavanols and subsequent absorption, causally modulate vascular function.
    American Journal of Clinical Nutrition 02/2012; 95(4):851-8. DOI:10.3945/ajcn.111.028340 · 6.92 Impact Factor
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    ABSTRACT: Accumulating data suggest that diets rich in flavanols and procyanidins are beneficial for human health. In this context, there has been a great interest in elucidating the systemic levels and metabolic profiles at which these compounds occur in humans. Although recent progress has been made, there still exist considerable differences and various disagreements with regard to the mammalian metabolites of these compounds, which in turn are largely a consequence of the lack of availability of authentic standards that would allow for the directed development and validation of expedient analytical methodologies. In this study, we developed a method for the analysis of structurally related flavanol metabolites using a wide range of authentic standards. Applying this method in the context of a human dietary intervention study using comprehensively characterized and standardized flavanol- and procyanidin-containing cocoa, we were able to identify the structurally related (-)-epicatechin metabolites (SREM) postprandially extant in the systemic circulation of humans. Our results demonstrate that (-)-epicatechin-3'-β-D-glucuronide, (-)-epicatechin-3'-sulfate, and a 3'-O-methyl-(-)-epicatechin-5/7-sulfate are the predominant SREM in humans and further confirm the relevance of the stereochemical configuration in the context of flavanol metabolism. In addition, we also identified plausible causes for the previously reported discrepancies regarding flavanol metabolism, consisting, to a significant extent, of interlaboratory differences in sample preparation (enzymatic treatment and sample conditioning for HPLC analysis) and detection systems. Thus, these findings may also aid in the establishment of consensus on this topic.
    Free Radical Biology and Medicine 12/2011; 52(8):1403-12. DOI:10.1016/j.freeradbiomed.2011.12.010 · 5.71 Impact Factor
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    ABSTRACT: Data on the potential health benefits of dietary flavanols and procyanidins, especially in the context of cardiovascular health, are considerable and continue to accumulate. Significant progress has been made in flavanol analytics and the creation of phytonutrient-content food databases, and novel data emanated from epidemiological investigations as well as dietary intervention studies. However, a comprehensive understanding of the pharmacological properties of flavanols and procyanidins, including their precise mechanisms of action in vivo, and a conclusive, consensus-based accreditation of a causal relationship between intake and health benefits in the context of primary and secondary cardiovascular disease prevention is still outstanding. Thus, the objective of this review is to identify and discuss key questions and gaps that will need to be addressed in order to conclusively demonstrate whether or not dietary flavanols and procyanidins have a role in preventing, delaying the onset of, or treating cardiovascular diseases, and thus improving human life expectancy and quality of life.
    Molecular Aspects of Medicine 12/2010; 31(6):546-57. DOI:10.1016/j.mam.2010.09.008 · 10.30 Impact Factor
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    ABSTRACT: Extensive epidemiological and clinical evidence associates diets high in flavanol-containing foods with cardiovascular health benefits in humans. Catechin and epicatechin, the most common flavanols in foods, are present in the diet in different enantiomeric forms. This study investigated the influence of the stereochemical configuration of flavanols on their absorption, metabolism, and biological activity. Healthy adult males were asked to consume equal amounts of the stereochemically pure flavanols (-)-epicatechin, (-)-catechin, (+)-catechin, and (+)-epicatechin (1.5mg/kg bw) in a well-defined cocoa-based, dairy-containing drink matrix, and flavanol levels were subsequently determined in plasma and 24-h urine. The results obtained show that the stereochemical configuration of flavanols has a profound influence on their uptake and metabolism in humans. In addition, we assessed the vasodilatory activity of each flavanol stereoisomer in vivo and found (-)-epicatechin to be the single stereoisomer capable of mediating a significant arterial dilation response. Importantly, this effect was independent of the classic antioxidant properties of flavanols. Overall, these results indicate that the proposed beneficial health effects associated with the consumption of flavanol-containing foods will significantly depend on the stereochemical configuration of the flavanols ingested.
    Free Radical Biology and Medicine 11/2010; 50(2):237-44. DOI:10.1016/j.freeradbiomed.2010.11.005 · 5.71 Impact Factor
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    ABSTRACT: The first enantioselective syntheses of sulfur flavan-3-ol analogues 1-8 have been accomplished, whereby the oxygen atom of the pyran ring has been replaced by a sulfur atom. The key steps were: (a) Pd(0) catalyzed introduction of -S t-butyl group, (b) Sharpless enantioselective dihydroxylation of the alkene, (c) acid catalyzed ring closure to produce the thiopyran ring, and (d) removal of benzyl groups using N,N-dimethylaniline and AlCl(3). The compounds were isolated in high chemical and optical purity.
    Molecules 08/2010; 15(8):5595-619. DOI:10.3390/molecules15085595 · 2.10 Impact Factor
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    ABSTRACT: The first synthesis of doubly labeled, [2-13C, 4-13C]-(2R,3S)-catechin 15 and [2-13C, 4-13C]-(2R,3R)-epicatechin 18 starting from labeled 2-hydroxy-4, 6-bis(benzyloxy)acetophenone 3 and labeled 3, 4-bis(benzyloxy)-benzaldehyde 7 are described. Copyright © 2010 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 08/2010; DOI:10.1002/jlcr.1791
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    ABSTRACT: In patients with coronary artery disease (CAD) medically managed according to currently accepted guidelines, we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells (CACs). Dietary flavanols can improve endothelial dysfunction. The CACs, also termed endothelial progenitor cells, are critical for vascular repair and maintenance of endothelial function. In a randomized, controlled, double-masked, cross-over trial, 16 CAD patients (64+/-3 years of age) received a dietary high-flavanol intervention (HiFI [375 mg]) and a macronutrient- and micronutrient-matched low-flavanol intervention (LoFI [9 mg]) twice daily in random order over 30 days. Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period. After HiFI, the number of CD34+/KDR+-CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI. The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups. The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: -4.2+/-2.7 mm Hg), and increase in plasma nitrite level (mean change over LoFI: 74+/-32 nM). Applying a mixed-effects linear regression model, the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs. Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs. (Effect of Cocoa Flavanols on Vascular Function in Optimally Treated Coronary Artery Disease Patients: Interaction Between Endothelial Progenitor Cells, Reactivity of Micro- and Macrocirculation; NCT00553774).
    Journal of the American College of Cardiology 07/2010; 56(3):218-24. DOI:10.1016/j.jacc.2010.03.039 · 15.34 Impact Factor

Publication Stats

3k Citations
268.95 Total Impact Points

Institutions

  • 2009–2015
    • Mars, Inc.
      Маклин, Virginia, United States
  • 2003–2013
    • University of California, Davis
      • Department of Nutrition
      Davis, California, United States
  • 1996–2010
    • University of Leipzig
      • Institute of Pharmacy
      Leipzig, Saxony, Germany
  • 2001–2007
    • King's College London
      • Wolfson Centre for Age-Related Diseases
      Londinium, England, United Kingdom
    • ICL
      Londinium, England, United Kingdom
    • University of Bath
      • Department of Pharmacy and Pharmacology
      Bath, England, United Kingdom
  • 2006
    • University of California, San Francisco
      • Division of Cardiology
      San Francisco, CA, United States
  • 2002
    • The King's College
      Charlotte, North Carolina, United States