Inhibidores de calpaina

Referencia OEPM: P200301125.-- Fecha de solicitud: 14/05/2003.-- Titular: Consejo Superior de Investigaciones Científicas (CSIC).La presente invención se refiere a compuestos que tienen estructura de híbrido péptido-bifenilo y compuestos relacionados con actividad como inhibidores de calpaina. Un compuesto de la presente invención es un bifenilo 2,2'-disustituido, siendo los sustituyentes en las posiciones 2 y 2' del esqueleto de bifenilo cadenas conteniendo estructuras relacionados con los aminoácidos, péptidos y amidas, que pueden ser iguales o distintos. La presente invención también engloba cualquiera de los isómeros conformacionales (atropisómeros) de dicho compuesto de fórmula I. Los compuestos de fórmula I tienen aplicación en el tratamiento preventivo o terapéutico de una enfermedad degenerativa.Peer reviewe

Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes

A series of 73 bisphosphonium salts and 10 monophosphonium salt derivatives were synthesized and tested in vitro against several wild type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48). More than half of the compounds tested showed a submicromolar EC 50 against these parasites. The compounds did not display any cross-resistance to existing diamidine therapies, such as pentamidine. In most cases, the compounds displayed a good selectivity index versus human cell lines. None of the known T. b. brucei drug transporters were required for trypanocidal activity, although some of the bisphosphonium compounds inhibited the low affinity pentamidine transporter. It was found that phosphonium drugs act slowly to clear a trypanosome population but that only a short exposure time is needed for irreversible damage to the cells. A comparative molecular field analysis model (CoMFA) was generated to gain insights into the SAR of this class of compounds, identifying key features for trypanocidal activity. © 2012 American Chemical Society.Peer Reviewe

Trends in incidence and outcomes of revision total hip arthroplasty in Spain: A population based study

<p>Abstract</p> <p>Background</p> <p>To analyze changes in incidence and outcomes of patients undergoing revision total hip arthroplasty (RTHA) over an 8-year study period in Spain.</p> <p>Methods</p> <p>We selected all surgical admissions in individuals aged ≥ 40 years who underwent RTHA (ICD-9-CM procedure code 81.53) between 2001 and 2008 from the Spanish National Hospital Discharge Database. Age- and sex-specific incidence rates, Charlson co-morbidity index, length of stay (LOS), costs and in-hospital mortality (IHM) were estimated for each year. Multivariate analyses were conducted to asses time trends.</p> <p>Results</p> <p>32, 280 discharges of patients (13, 391 men/18, 889 women) having undergone RTHA were identified. Overall crude incidence showed a small but significant increase from 20.2 to 21.8 RTHA per 100, 000 inhabitants from 2001 to 2008 (p < 0.01).</p> <p>The incidence increased for men (17.7 to 19.8 in 2008) but did not vary for women (22.3 in 2001 and 22.2 in 2008). Greater increments were observed in patients older than 84 years and in the age group 75-84. In 2001, 19% of RTHA patients had a Charlson Index ≥ 1 and this proportion rose to 24.6% in 2008 (p < 0.001). The ratio RTHA/THA remained stable and around 20% in Spain along the entire period</p> <p>The crude overall in-hospital mortality (IHM) increased from 1.16% in 2001 to 1.77% (p = 0.025) in 2008. For both sexes the risk of death was higher with age, with the highest mortality rates found among those aged 85 or over. After multivariate analysis no change was observed in IHM over time. The mean inflation adjusted cost per patient increased by 78.3%, from 9, 375 to 16, 715 Euros from 2001 to 2008.</p> <p>After controlling for possible confounders using Poisson regression models, we observed that the incidence of RTHA hospitalizations significantly increased for men and women over the period 2001 to 2008 (IRR 1.10, 95% CI 1.03-1.18 and 1.08, 95% CI 1.02-1.14 respectively).</p> <p>Conclusions</p> <p>The crude incidence of RTHA in Spain showed a small but significant increase from 2001 to 2008 with concomitant reductions in LOS, significant increase in co-morbidities and cost per patient.</p

Exemples de QSAR sur des coefficients de partage

National audienc

Flavor Release from i-Carrageenan Matrix: A Quantitative Structure-Property Relationships Approach

International audienceWe carried out a QSPR (quantitative structure-property relationships) approach to evaluate the influence of the chemical structure of aqueous matrixes over the partition coefficient between the gas phase and the matrix. The determination of the partition coefficient of flavor ingredients was performed by headspace analysis at equilibrium for both saline solution and -carrageenan gel. Starting from an initial list of 90 descriptors, we selected 10 descriptors to perform equation generation by the GFA (genetic function approximation) method available in the Cerius2 package. The best obtained equations involve only five descriptors, which encode electronic properties of charges repartition on the molecule (Jurs-RNCS and Dipole-Z) and molecules' shapes (PMI-Y, Shadow-XY, and RadOfGyration), both for saline solution and for -carrageenan gel. However, the best-fitting equation for carrageenan gel is obtained with a quadratic relation, suggesting that the effect of carrageenan polymers only modulates but does not change the interaction of aroma compounds with water molecules

Flavor Release from i-Carrageenan Matrix: A Quantitative Structure-Property Relationships Approach

International audienceWe carried out a QSPR (quantitative structure-property relationships) approach to evaluate the influence of the chemical structure of aqueous matrixes over the partition coefficient between the gas phase and the matrix. The determination of the partition coefficient of flavor ingredients was performed by headspace analysis at equilibrium for both saline solution and -carrageenan gel. Starting from an initial list of 90 descriptors, we selected 10 descriptors to perform equation generation by the GFA (genetic function approximation) method available in the Cerius2 package. The best obtained equations involve only five descriptors, which encode electronic properties of charges repartition on the molecule (Jurs-RNCS and Dipole-Z) and molecules' shapes (PMI-Y, Shadow-XY, and RadOfGyration), both for saline solution and for -carrageenan gel. However, the best-fitting equation for carrageenan gel is obtained with a quadratic relation, suggesting that the effect of carrageenan polymers only modulates but does not change the interaction of aroma compounds with water molecules

Peptide-biphenyl hybrids as calpain inhibitors

16 pages, 7 figures.-- PMID: 17191858 [PubMed].-- Taken in part from the Ph.D. thesis of A. C. (December, 2003) and the projected Ph.D. thesis of A. M. Spanish patent ES-P200301125 was filed as of Feb 16, 2006.Calpain is a cysteine protease that is activated by Ca2+. The over-activation of calpain, which occurs on increasing Ca2+ concentration, causes a variety of diseases. This paper reports experimental results on the inhibition of calpain I (μ-calpain) by peptide-biphenyl hybrids. We have found that some peptide-biphenyl hybrids, with aromatic amino acids in the peptide chains, inhibit calpain with IC50 values in the nanomolar range. Since the peptide-biphenyl hybrids reported in the present paper do not posses a reactive electrophilic functionality, we hypothesize that they interfere with the activation of calpain by Ca2+, and present experimental and computational results on the binding of peptide-biphenyl hybrids to Ca2+.Financial support from the Spanish Ministry of Science and Technology (project No. BQU2001-2270) and Fundación 'la Caixa' (project No. 02/162-02) is acknowledged.Peer reviewe

Gas phase acidity measurement of local acidic groups in multifunctional species: Controlling the binding sites in hydroxycinnamic acids

10 pags, 7 figs, 2 tabs. -- Supporting Information available at the Publisher's webThe applicability of the extended kinetic method (EKM) to determine the gas phase acidities (GA) of different deprotonable groups within the same molecule was tested by measuring the acidities of cinnamic, coumaric, and caffeic acids. These molecules differ not only in the number of acidic groups but in their nature, intramolecular distances, and calculated GAs. In order to determine independently the GA of groups within the same molecule using the EKM, it is necessary to selectively prepare pure forms of the hydrogen-bound heterodimer. In this work, the selectivity was achieved by the use of solvents of different vapor pressure (water and acetonitrile), as well as by variation of the drying temperature in the ESI source, which affected the production of heterodimers with different solvation energies and gas-phase dissociation energies. A particularly surprising finding is that the calculated solvation enthalpies of water and the aprotic acetonitrile are essentially identical, and that the different gas-phase products generated are apparently the result of their different vapor pressures, which affects the drying mechanism. This approach for the selective preparation of heterodimers, which is based on the energetics, appears to be quite general and should prove useful for other studies that require the selective production of heterodimers in ESI sources. The experimental results were supported by density functional theory (DFT) calculations of both gas-phase and solvated species. The experimental thermochemical parameters (deprotonation ΔG, ΔH, and ΔS) are in good agreement with the calculated values for the monofunctional cinnamic acid, as well as the multifunctional coumaric and caffeic acids. The measured GA for cinnamic acid is 334.5 ± 2.0 kcal/mol. The measured acidities for the COOH and OH groups of coumaric and caffeic acids are 332.7 ± 2.0, 318.7 ± 2.1, 332.2 ± 2.0, and 317.3 ± 2.2 kcal/mol, respectively. © 2013 American Chemical Society.This study was supported by a grant (Project. No. CTQ2009-13652) from the Spanish MEC/MICINN. A.G. thanks Prof. M. T. Rodgers for very helpful discussions during the Gordon Research Conference on Gaseous Ions: Structures, Energetics & Reactions, Galveston, 2011. We also thank the very helpful comments of three reviewers of this paper. T.B. is grateful for financial support from the Spanish MICINN (Ref. SAB2009-0028) for a four month visit to Madrid

Induction of cytochrome P4501A (CYP1A) by clotrimazole, a non-planar aromatic compound. Computational studies on structural features of clotrimazole and related imidazole derivatives

16 pages, 7 figures.-- PMID: 15567194 [PubMed].-- Printed version published on Dec 24, 2004.The classical pathway for induction of cytochrome P4501A (CYP1A) by xenobiotics is ligand binding to the aryl hydrocarbon receptor (AhR). High-affinity AhR ligands are planar polyaromatic molecules such as the prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The present work investigated the ability of the imidazole derivative, clotrimazole [1-(2′chlorotrityl)imidazole, CLO], to induce CYP1A in cultured rainbow trout (Oncorhynchus mykiss) hepatocytes at the catalytic activity (determined as 7-ethoxyresorufin-O-deethylase, EROD) and at the transcriptional level. CLO resulted in a significant increase of hepatocyte EROD activity and CYP1A mRNA at a concentration of 1.56 μM. Computational studies on the molecular structure of CLO show that CLO is unlikely to take a planar conformation. Further indications that CLO does not behave like a planar AhR ligand come from the experimental observation that co-incubation of trout hepatocytes with CLO and the AhR antagonist, α-naphthoflavone (α-NF), did not result in an inhibition of CLO induction of CYP1A mRNA, whereas α-NF was able to inhibit CYP1A induction by the prototpyic, planar AhR ligand, β-naphthoflavone. The experimental findings on CLO agree with previous results obtained for another non-planar imidazole derivative, 1-benzylimidazole (BIM). Further, computational studies showed that the non-planar imidazoles, BIM and CLO, are highly similar with respect to some electrostatic properties, namely the dipole moment and the molecular electrostatic potential (MEP). Overall our experimental and computational studies suggest that transcriptional activation of CYP1A by the imidazole derivatives CLO and BIM is mediated by a mechanism different to that of prototypic CYP1A inducers such as the planar AhR-ligands.José María Navas holds a Ramón y Cajal contract from the Spanish Ministry of Science and Technology (MCYT). This work was financially supported by MCYT projects (REN2002-00639/GLO and BQU2001-2270), and by CAM (Comunidad Autónoma de Madrid) project 07M/0032/2002.Peer reviewe