Frode Rise

A new palladium catalyst for intramolecular carbametalations of enynes

Abstract The combination of (dba) 3 Pd 2 ·CHCl 3 plus a car☐ylic acid effectively catalyzes cyclization of 1,6-enynes in which asymmetric induction may be achieved by use of enantiomerically pure car☐ylic acids.

Isolation, structural determination and acute toxicity of pinnatoxins E, F and G.

Pinnatoxins and pteriatoxins are a group of cyclic imine toxins that have hitherto only been isolated from Japanese shellfish. As with other cyclic imine shellfish toxins, pinnatoxins cause rapid death in the mouse bioassay for lipophilic shellfish toxins, but there is no evidence directly linking these compounds to human illness. We have identified the known pinnatoxins A (1) and D (6), and the novel pinnatoxins E (7), F (8) and G (5), in a range of shellfish and environmental samples from Australia and New Zealand using LC-MS. After isolation from the digestive glands of Pacific oysters, the structures of the novel pinnatoxins were determined by mass spectrometry and NMR spectroscopy, and their LD(50) values were evaluated by ip administration to mice. Examination of the toxin structures, together with analysis of environmental samples, suggests that pinnatoxins F and G are produced separately in different dinoflagellates. Furthermore, it appears probable that pinnatoxin F (8) is the progenitor of pinnatoxins D (6) and E (7), and that pinnatoxin G (6) is the progenitor of both pinnatoxins A-C (1 and 2) and pteriatoxins A-C (3 and 4), via metabolic and hydrolytic transformations in shellfish.

Synthesis of 1-substituted 7-cyano-2,3-diphenylindolizines and evaluation of antioxidant properties

Protocols for the synthesis of novel 1-substituted 7-cyano-2,3-diphenylindolizines from the corresponding indolizinol have been developed, and the compounds’ abilities to act as antioxidants, i.e. To inhibit lipid peroxidation in vitro, have been examined. 1-bromo-7-cyano-2,3-diphenylindolizine 9 readily participates in pd-catalysed coupling reactions with organotin, organozinc, and organoboron reagents. Similar treatment of the corresponding indolizinyl triflate 6, on the other hand, resulted only in partial cleavage of the triflate back to the indolizinol, except in reaction with 1-ethoxyethenyl(tributyl)tin. Here, the unexpected acetal (1-ethoxyethoxy)indolizine 10 was formed. The structure of 10 was determined by single-crystal x-ray diffraction methods at 150 k. An alternative strategy for the introduction of substituents at c-1 is by lithiation of the bromide 9 followed by reaction with electrophiles. The ability of the indolizine derivatives to inhibit lipid peroxidation in vitro was examined. Lipid peroxidation of boiled rat liver microsomes was induced by ascorbic acid/feso4 and peroxidation was determined by measuring the material reactive to thiobarbituric acid. In particular, the indolizinyl acetate 4 and the triflate 6 appear to be highly active antioxidants, with ic50 values below 1 µm in the bioassay.

6-Halopurines in palladium-catalyzed coupling with organotin and organozinc reagents

Abstract N-9 and N-7 benzylated 6-halopurines readily participate in palladium catalyzed cross coupling reactions with organotin and organozinc derivati

Regiochemistry in Stille couplings of 2,6-dihalopurines

Abstract The regiochemistry in Stille couplings of 2,6-dihalopurines have been studied. 2,6-Dichloropurines react selectively in the 6-position, and 6-chloro-2-iodopurines and 2-bromo-6-chloropurines in the 2-position.

Synthesis of 6-alkenyl- and 6-alkynylpurines with cytokinin activity

Abstract Analogs of the cytokinins trans -zeatin and benzylaminopurine have been prepared by Heck coupling on 6-vinylpurines or Sonogashira coupling on 6-halopurines as key-steps, and their cytokinin activity has been evaluated based on their ability to stimulate increased growth in radish cotyledons.

Brain metabolism of exogenous pyruvate

Pyruvate given in large doses may be neuroprotective in stroke, but it is not known to what degree the brain metabolizes pyruvate. Intravenous injection of [3‐13C]pyruvate led to dose‐dependent labelling of cerebral metabolites so that at 5 min after injection of 18 mmoles [3‐13C]pyruvate/kg (2 g sodium pyruvate/kg), approximately 20% of brain glutamate and GABA were labelled, as could be detected by 13C nuclear magnetic resonance spectrometry ex vivo. Pyruvate, 9 mmoles/kg, was equivalent to glucose, 9 mmoles/kg, as a substrate for cerebral tricarboxylic acid (TCA) cycle activity. Inhibition of the glial TCA cycle with fluoroacetate did not affect formation of [4‐13C]glutamate or [2‐13C]GABA from [3‐13C]pyruvate, but reduced formation of [4‐13C]glutamine by 50%, indicating predominantly neuronal metabolism of exogenous pyruvate. Extensive formation of [3‐13C]lactate from [2‐13C]pyruvate demonstrated reversible carboxylation of pyruvate to malate and equilibration with fumarate, presumably in neurones, but anaplerotic formation of TCA cycle intermediates from exogenous pyruvate could not be detected. Too rapid injection of large amounts of pyruvate led to seizure activity, respiratory arrest and death. We conclude that exogenous pyruvate is an excellent energy substrate for neurones in vivo, but that care must be taken to avoid the seizure‐inducing effect of pyruvate given in large doses.

Cytotoxic and Antibacterial Activity of 2-Oxopurine Derivatives

Initial screening of the cytotoxic and antibacterial properties of 6-substituted 2-oxopurines and dihydro-2-oxopurines revealed that several compounds exhibited cytotoxicity against K-562 cells in the same range as the well known antileukemic drug 6-mercaptopurine. Most compounds were also tested for inhibitory effect on a Gram-positive bacterium, Lactobacillus casei, as well as the mycobacterium Mycobacterium tuberculosis. Generally the 2-oxopurines exhibited low antibacterial effect.

Metabolic Changes in Urine during and after Pregnancy in a Large, Multiethnic Population-Based Cohort Study of Gestational Diabetes

This study aims to identify novel markers for gestational diabetes (GDM) in the biochemical profile of maternal urine using NMR metabolomics. It also catalogs the general effects of pregnancy and delivery on the urine profile. Urine samples were collected at three time points (visit V1: gestational week 8–20; V2: week 28±2; V3∶10–16 weeks post partum) from participants in the STORK Groruddalen program, a prospective, multiethnic cohort study of 823 healthy, pregnant women in Oslo, Norway, and analyzed using 1H-NMR spectroscopy. Metabolites were identified and quantified where possible. PCA, PLS-DA and univariate statistics were applied and found substantial differences between the time points, dominated by a steady increase of urinary lactose concentrations, and an increase during pregnancy and subsequent dramatic reduction of several unidentified NMR signals between 0.5 and 1.1 ppm. Multivariate methods could not reliably identify GDM cases based on the WHO or graded criteria based on IADPSG definitions, indicating that the pattern of urinary metabolites above micromolar concentrations is not influenced strongly and consistently enough by the disease. However, univariate analysis suggests elevated mean citrate concentrations with increasing hyperglycemia. Multivariate classification with respect to ethnic background produced weak but statistically significant models. These results suggest that although NMR-based metabolomics can monitor changes in the urinary excretion profile of pregnant women, it may not be a prudent choice for the study of GDM.

Propionate increases neuronal histone acetylation, but is metabolized oxidatively by glia. Relevance for propionic acidemia

In propionic acidemia, propionate acts as a metabolic toxin in liver cells by accumulating in mitochondria as propionyl‐CoA and its derivative, methylcitrate, two tricarboxylic acid cycle inhibitors. Little is known about the cerebral metabolism of propionate, although clinical effects of propionic acidemia are largely neurological. We found that propionate was metabolized oxidatively by glia: [3‐14C]propionate injected into mouse striatum or cortex, gave a specific activity of glutamine that was 5–6 times that of glutamate, indicating metabolism in cells that express glutamine synthetase, i.e., glia. Further, cultured cerebellar astrocytes metabolized [3‐14C]propionate; cultured neurons did not. However, both cultured cerebellar neurons and astrocytes took up [3H]propionate, and propionate exposure increased histone acetylation in cultured neurons and astrocytes as well as in hippocampal CA3 pyramidal neurons of wake mice. The inability of neurons to metabolize propionate may be due to lack of mitochondrial propionyl‐CoA synthetase activity or transport of propionyl residues into mitochondria, as cultured neurons expressed propionyl‐CoA carboxylase, a mitochondrial matrix enzyme, and oxidized isoleucine, which becomes converted into propionyl‐CoA intramitochondrially. The glial metabolism of propionate suggests astrocytic vulnerability in propionic acidemia when intramitochondrial propionyl‐CoA may accumulate. Propionic acidemia may alter both neuronal and glial gene expression by affecting histone acetylation.