PMR investigation of organic cations—I: Trithienyl methyl carbonium ions

PMR spectral parameters are reported for the isomeric trithienyl carbonium ions. The low field shifts, relative to the corresponding carbinols, are discussed in relation to the delocalization of the positive charge into the thiophene ring bonded in position 2 or 3. A linear correlation is found between chemical shifts and π-charge densities and the proportionality constant is higher than that previously found for benzene derivatives. Vicinal coupling constants in these systems are satisfactorily in agreement with the corresponding calculated π-bond order.     

Convenient synthetic approach to 2,4-disubstituted quinazolines

[reaction: see text] 2,4-Dialkyl or aryl quinazolines have been prepared in three steps starting from easily available anilides. A photochemically induced Fries rearrangement of the anilides gave several ortho-aminoacylbenzene derivatives that were acylated at the NH2. These acylamides underwent rapid cyclization to 2,4-disubstituted quinazolines (and benzoquinazolines) in the presence of ammonium formate under microwave activation. This procedure is compatible with different functional groups and allowed also the preparation of new quinazolines derived from naturally occurring amino acids.     

Synthesis of functionalized quinolines and benzo[c][2,7]naphthyridines based on a photo-Fries rearrangement

An efficient one-pot method for the synthesis of functionalized quinolines and tetrahydronaphthyridines has been developed. The photo-Fries rearrangement of p-substituted anilides afforded differently substituted o-amino ketones that reacted in situ with acetylenic Michael acceptors such as dimethyl acetylenedicarboxylate (DMAD) to give 6,4-disubstituted quinoline 2,3-dicarboxylates. Starting from anilides derived from β-alanine, a naphthyridine nucleus can also be assembled.     

Progranulin is expressed within motor neurons and promotes neuronal cell survival

Background

Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival.

Results

In situ hybridisation and immunohistochemical techniques revealed that the progranulin gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human progranulin gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival.

Conclusion

Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.     

Variable temperature n.m.r. behaviour of 1,5-benzodiazepinones and 1,5-benzodiazepinthiones

The n.m.r. variable temperature behaviour of the 7-membered ring in 1,3-dihydro-2H-1,5-benzodiazepin-2-one derivatives and in the corresponding 2-thiones has been investigated. The results indicate that the ring inversion barrier is higher in the thiones and dependent on substituents bonded at N-1. The activation parameters are obtained and discussed.     

Rare earth elements in sediment profiles from marginal lagoons of the Moji-Guaçu River basin, Brazil

Summary Sediment cores from Catingueiro, Barrinha and Rio das Pedras marginal lagoons of the Moji-Gua?u River basin were analyzed for rare earth elements (REEs), Fe, Ta and Th by instrumental neutron activation analysis (k₀-INAA). Data indicated similarities between Catingueiro and Barrinha lagoons, while a distinct scenario was seen for Rio das Pedras likely due to changes of sedimentation rate in 1950's. By using Fe, Sc, Ta and Th as conservative elements, double normalization technique was performed in order to assess the distribution pattern of Ce, Eu, La, Sm and Tb for each core. In all cases, it was evident a depletion of lighter REE elements in the Rio das Pedras lagoon.