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Abboud J.-L.M.,Kyushu University | Alkorta I.,Institute of Medical Chemistry | Davalos J.Z.,CSIC - Institute of Polymer Science and Technology | Koppel I.A.,CSIC - Institute of Physical Chemistry "Rocasolano" | And 4 more authors.
Bulletin of the Chemical Society of Japan | Year: 2016

We report herein the results of an experimental and computational study of adamantylideneadamantane (1) and a variety of substituted ethylenic hydrocarbons. The standard enthalpy of formation in the gas phase as well as the gas-phase basicity (GA) of 1 were experimentally determined for the first time, respectively by calorimetric techniques and FT-ICR spectrometry. In parallel, computational studies at the MP2/ 6-311+G(d,p), G3(MP2), and G3 levels were performed on the neutral (1) and protonated (1H+ ). The agreement with experimental results was very good. The structures of 1 and1H+ were subject to treatment by "Atoms in Molecules" in order to assess the characteristics of the closest H£H interactions involving both adamantane moieties. Also, the secondorder perturbation analysis within the Natural Bond Orbital Theory methodology shows four degenerate charge-transfer interactions between the ó C?H bond of one of the adamantyl subunits towards the ó∗ C?H of the other adamantyl subunit. The standard enthalpies of formation of new adamantyl compounds were obtained using our experimental data. The computational study of a variety of ethylenic compounds including cyclohexylidenecyclohexane and several alkyl-substituted ethylenes using isodesmic and homodesmotic reactions was carried out. This study was extended to their proton affinities and gas-phase basicities. © 2016 The Chemical Society of Japan.

Chiba P.,Institute of Medical Chemistry | Freissmuth M.,Medical University of Vienna | Stockner T.,Medical University of Vienna
Pharmacological Research | Year: 2014

SLC6 family members and ABC transporters represent two extremes: SLC6 transporters are confined to the membrane proper and only expose small segments to the hydrophilic milieu. In ABC transporters the hydrophobic core is connected to a large intracellular (eponymous) ATP binding domain that is comprised of two discontiguous repeats. Accordingly, their folding problem is fundamentally different. This can be gauged from mutations that impair the folding of the encoded protein and give rise to clinically relevant disease phenotypes: in SLC6 transporters, these cluster at the protein-lipid interface on the membrane exposed surface. Mutations in ABC-transporters map to the interface between nucleotide binding domains and the coupling helices, which provide the connection to the hydrophobic core. Folding of these mutated ABC-transporters can be corrected with ligands/substrates that bind to the hydrophobic core. This highlights a pivotal role of the coupling helices in the folding trajectory. In contrast, insights into pharmacochaperoning of SLC6 transporters are limited to monoamine transporters - in particular the serotonin transporter (SERT) - because of their rich pharmacology. Only ligands that stabilize the inward facing conformation act as effective pharmacochaperones. This indicates that the folding trajectory of SERT proceeds via the inward facing conformation. Mutations that impair folding of SLC6 family members can be transmitted as dominant or recessive alleles. The dominant phenotype of the mutation can be rationalized, because SLC6 transporters are exported in oligomeric form from the endoplasmic reticulum (ER). Recessive transmission requires shielding of the unaffected gene product from the mutated transporter in the ER. This can be accounted for by a chaperone-COPII (coatomer protein II) exchange model, where proteinaceous ER-resident chaperones engage various intermediates prior to formation of the oligomeric state and subsequent export from the ER. It is likely that the action of pharmacochaperones is contingent on and modulated by these chaperones. © 2013 The Authors.

Crespillo A.,Laboratorio Of Medicina Regenerativa | Alonso M.,Laboratorio Of Medicina Regenerativa | Vida M.,Laboratorio Of Medicina Regenerativa | Pavon F.J.,Laboratorio Of Medicina Regenerativa | And 12 more authors.
British Journal of Pharmacology | Year: 2011

BACKGROUND AND PURPOSE The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats. EXPERIMENTAL APPROACH Rats made obese after exposure to a very (60%) high fat-content diet were treated with daidzein (50 mg·kg -1) for 14 days. The dose was selected on the basis of the acute effects of this isoflavone on a feeding test. After 14 days, animals were killed and plasma, white and brown adipose tissue, muscle and liver studied for the levels and expression of metabolites, proteins and genes relevant to lipid metabolism. KEY RESULTS A single treatment (acute) with daidzein dose-dependently reduced food intake. Chronic treatment (daily for 14 days) reduced weight gain and fat content in liver, accompanied by high leptin and low adiponectin levels in plasma. While skeletal muscle was weakly affected by treatment, both adipose tissue and liver displayed marked changes after treatment with daidzein, affecting transcription factors and lipogenic enzymes, particularly stearoyl coenzyme A desaturase 1, a pivotal enzyme in obesity. Expression of uncoupling protein 1, an important enzyme for thermogenesis, was increased in brown adipose tissue after daidzein treatment. CONCLUSIONS AND IMPLICATIONS These results support the use of isoflavones in diet-induced obesity, especially when hepatic steatosis is present and open a new field of use for these natural products. © 2011 The British Pharmacological Society.

Temprado M.,CSIC - Institute of Physical Chemistry "Rocasolano" | Temprado M.,University of Alcala | Roux M.V.,CSIC - Institute of Physical Chemistry "Rocasolano" | Ros F.,Institute of Medical Chemistry | And 3 more authors.
Journal of Chemical and Engineering Data | Year: 2011

The present study reports a differential scanning calorimetry (DSC) study of the barbituric acid derivatives: 1,3-dimethylbarbituric acid [CAS 769-42-6], 5,5-dimethylbarbituric acid [CAS 24448-94-0], 1,3-diethylbarbituric acid [CAS 32479-73-5], 1,3,5-trimethylbarbituric acid [CAS 7358-61-4], 1,5,5-trimethylbarbituric acid [CAS 702-47-6], and tetramethylbarbituric acid [CAS 13566-66-0] in the temperature interval from T = 268 K to their respective melting temperatures. Temperatures, enthalpies and entropies of fusion, and the heat capacities of the solid compounds as a function of temperature are reported. © 2010 American Chemical Society.

Donnelly M.P.,Yale University | Paschou P.,Democritus University of Thrace | Grigorenko E.,Yale University | Gurwitz D.,National Laboratory for the Genetics of Israeli Populations | And 20 more authors.
American Journal of Human Genetics | Year: 2010

The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an ∼900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of ∼30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the ∼900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.1. © 2010 The American Society of Human Genetics.

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