Tammo Winkler

The metabolism of 14C-oxcarbazepine in man

The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of 14C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Faecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary 14C. Unchanged oxcarbazepine, and its sulphate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favouring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.

13C NMR spectroscopy of naturally occurring iridoid glucosides and their acylated derivatives

Abstract The 13 C NMR spectra of twenty one iridoid glucosides and fourteen acyl iridoid glucosides of various cyclopentane oxidation states have been analysed and their carbon shifts assigned. Evidence is presented which demonstrates that 13 C NMR spectroscopy is a valuable and reliable technique for distinguishing the sites of acylation in iridoid glucosides and confirming the predictions of the configuration at C-6 and C-8. A cis configuration of vicinal substituents is generally associated with a substantial increase in shielding, as compared with the trans analog. The ring size and C-1 configuration in the glucose moiety are also evident from the spectra.

Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose

1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a 14C-labelled preparation as a neutral buffered solution. 2. Peak concentrations of radioactivity and valsartan in plasma measured 1 h after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed. 3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at time points later than 2 h after dosing, representing approximately 11% of the AUC(24 h) of plasma radioactivity. 4. The bulk of the dose was excreted within 4 days. The total excretion within 7 days amounted to 99 +/- 1% of dose. Faecal excretion was predominant (86 +/- 5% of dose). Valsartan was largely excreted unchanged (81 +/- 5% of the dose in the excreta). The predominant clearance mechanism appeared to be direct elimination via bile. 5. An inactive metabolite, M1, was formed by oxidative biotransformation and accounted for 9 +/- 3% of the dose in the excreta.

Syringolin, a novel peptide elicitor from Pseudomonas syringae pv. syringae that induces resistance to Pyricularia oryzae in rice

Recognition by rice plants (Oryza sativa) of the nonhost pathogen Pseudomonas syringae pv. syringae leads to an active response ultimately resulting in local acquired resistance against the rice blast fungus Pyricularia oryzae. An observable aspect of this defense response is the increased abundance of a set of transcripts. The accumulation of one of these transcripts, Pir7b, was dependent on the function of the bacterial lemA gene, which encodes part of a two-component regulatory system. This suggested that the lemA regulatory system controlled the production of an elicitor of Pir7b transcript accumulation. This elicitor, which we name syringolin, was purified to homogeneity and its structure was elucidated. Syringolin is a novel and unusual secreted peptide consisting of a 12-membered ring formed by the two non-proteinogenic amino acids 5-methyl-4-amino-2-hexenoic acid and 3,4-dehydrolysine. The α-amino group of the latter is connected by a peptide bond to a valine that in turn is linked to a second val...

Preparation of glycosyl halides under neutral conditions

Abstract The anomeric hydroxyl group of various furanose and pyranose hemiacetals can be replaced by a fluorine, chlorine, bromine or iodine atom under neutral conditions using haloenamines.

Convenient approaches to heterocycles via copper-catalysed additions of organic polyhalides to activated olefins

Abstract An efficient method for the synthesis of 2,3-dichloro-5-substituted (Cl, CF3, alkyl) pyridines 29 starting from the 1:1 adducts of the copper-catalysed addition of chloral or the corresponding 2,2-dichloroaldehydes to acrylonitrile is presented. Proper choice of experimental conditions allows the preparation of 29 in a one-pot process. Similarly, the CuCl-catalysed reaction of methyl itaconate with several trichloromethyl compounds R-CCl3 gives 6-R-substituted 2-pyrone derivatives 40 via dehalogenation and subsequent thermal ring closure of the primary 1:1-adducts. The new electrophilic 2-pyrone 40b undergoes [4+2]-cycloaddition reactions with inverse electron demand with a number olefins and acetylenes, allowing thereby regioselective transfer of a trifluoromethyl group from a simple Freon derivative (1,1,1-trichloro-2,2,2-trifluoroethane) into more complex organic molecules. Finally, the 1:1-adduct of trichloroacetylchloride with methyl acrylate allows a very convenient synthesis of novel N-substituted derivatives 66 of pyroglutamic acid as well as of proline.

Oviposition stimulants for the cabbage root fly: isolation from cabbage leaves

Abstract Two compounds present on the surface of Brassica oleracea cv. botrytis leaves have been isolated and identified which stimulate very effectively oviposition in the cabbage root fly, Delia radicum and which are perceived by a specific receptor neuron in the tarsal sensillum C5 of the female fly. Activity of extracts and chromatographic fractions were bioassayed, using oviposition experiments and mainly electrophysiological recordings from the C5 tarsal contact chemoreceptor sensillum of female flies. Spectroscopic data indicate that the main compound is 1,2-dihydro-3-thia-4,10,10b-triaza-cyclopenta[.a.]fluorene-1-carboxylic acid, a novel compound related to Brassica phytoalexins like brassicanal C. It is accompanied by its glycine conjugate.

Identification and structure of a family of syringolin variants : Unusual cyclic peptides from Pseudomonas syringae pv. syringae that elicit defense responses in rice

Abstract Pseudomonas syringae pv. syringae is recognized by the non-host plant Oryza sativa which reacts with defense responses leading to induced resistance towards the rice blast fungus Pyricularia oryzae . We have previously shown that syringolin, a novel and unusual peptide secreted by P. syringae pv. syringae under appropriate conditions, is one of the molecular determinants by which rice plants can perceive the non-host pathogen. Here we show that syringolin is a member of a family of related compounds. We have isolated syringolin variants B to F and determined their structure using mass and NMR spectroscopic methods. These variants, which differ from each other by various modifications, are all able to induce defense responses upon application onto rice leaves.

Enzymatic synthesis of β-D-glucuronides with in situ regeneration of uridine 5′-diphosphoglucuronic acid

Abstract β-D-glucuronides of 1 and 2 have been synthesized by a multi-enzyme system with in situ regeneration of uridine 5′-diphosphoglucuronic acid. Crude liver homogenate containing all enzymes involved in the multi-enzyme system was used for this stereoselective one-pot reaction.

Stereoselective CC bond formation in carbohydrates by radical cyclization reactions-III. Strategy for the preparation of C(1)-glycosides

Abstract A new strategy for the stereoselective synthesis of α- and β-C(1)-glycosides based on an intramolecular radical cyclization reaction is described. Intramolecular hydrogen atom transfer was observed depending on the concentration of the reagents, the conformation and the substitution of the cyclized radical.