4-Anilinoquinazoline Derivatives as the First Potent NOD1-RIPK2 Signaling Pathway Inhibitors at the Nanomolar Range.

Inflammation is a defense mechanism that restores tissue damage and eliminates pathogens. Among the pattern recognition receptors that recognize danger or pathogenic signals, nucleotide oligomerization domains 1 and 2 (NOD1/2) have been identified to play an important role in innate immunity responses, and inhibition of NOD1 could be interesting to treat severe infections and inflammatory diseases. In this work, we identified the first selective NOD1 versus NOD2 pathway inhibitors at the nanomolar range based on a 4-anilinoquinazoline scaffold.

One- or Two-Step Synthesis of C-8 and N-9 Substituted Purines.

A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and hydrazine, respectively.

Repetitive TMS of the temporo-parietal junction disrupts participant's expectations in a spontaneous Theory of Mind task.

A recent debate about Theory of Mind (ToM) concerns whether spontaneous and explicit mentalizing are based on the same mechanisms. However, only a few neuroimaging studies have investigated the neural bases of spontaneous ToM, with inconsistent results. The present study had two goals: first, to investigate whether the right Temporo-Parietal Junction (rTPJ) is crucially involved in spontaneous ToM and second, to gain insight into the role of the rTPJ in ToM.

Chiral separation of new sulfonamide derivatives and evaluation of their enantioselective affinity for human carbonic anhydrase II by microscale thermophoresis and surface plasmon resonance.

The aim of this study was to develop a method combining chiral separation and biophysical techniques to evaluate the enantioselective affinity of original sulfonamide derivatives towards their therapeutic target, the human carbonic anhydrase II (hACII). The first step consisted in the preparation of the enantiomers by chromatographic separation. The performances of HPLC and Supercritical Fluid Chromatography (SFC) were studied at the analytical scale by optimization of various experimental conditions using adsorbed polysaccharide chiral stationary phases (amylose AD-H and cellulose OD-H).

Using Spontaneous Emission of a Qubit as a Resource for Feedback Control.

Persistent control of a transmon qubit is performed by a feedback protocol based on continuous heterodyne measurement of its fluorescence. By driving the qubit and cavity with microwave signals whose amplitudes depend linearly on the instantaneous values of the quadratures of the measured fluorescence field, we show that it is possible to stabilize permanently the qubit in any targeted state. Using a Josephson mixer as a phase-preserving amplifier, it was possible to reach a total measurement efficiency η=35%, leading to a maximum of 59% of excitation and 44% of coherence for the stabilized states.

Amine coupling versus biotin capture for the assessment of sulfonamide as ligands of hCA isoforms.

This work was dedicated to the development of a reliable SPR method allowing the simultaneous and quick determination of the affinity and selectivity of designed sulfonamide derivatives for hCAIX and hCAXII versus hCAII, in order to provide an efficient tool to discover drugs for anticancer therapy of solid tumors. We performed for the first time a comparison of two immobilization approaches of hCA isoforms. First one relies on the use of an amine coupling strategy, using a CM7 chip to obtain higher immobilization levels than with a CM5 chip and consequently the affinity with an higher precision (CV% < 10%).

Inhibition of tumor cell growth and angiogenesis by 7-aminoalkoxy-4-aryloxy-quinazoline ureas, a novel series of multi-tyrosine kinase inhibitors.

Several regulatory and signaling molecules governing angiogenesis are targets of interest for the development of drugs in the cancer, including growth factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF). A series of 4-aryloxy-6,7-dimethoxyquinazolines, previously synthesized in our laboratory, has shown a nanomolar inhibition of kinase enzymatic activity of VEGFR, PDGFR and c-Kit. We have therefore studied the impact of the variation in the 7-position substitution of the quinazoline core.

Optimization of the enantioseparation of a diaryl-pyrazole sulfonamide derivative by capillary electrophoresis in a dual CD mode using experimental design.

A CE method using dual cationic and neutral cyclodextrins (CD) was optimized for the enantiomeric separation of a compound presenting a diaryl sulfonamide group. Preliminary studies were made to select the optimal CDs and pH of the BGE. Two CDs (amino-β-CD and β-CD) were selected to separate the enantiomers in a 67 mM phosphate buffer at pH 7.

Label-free characterization of carbonic anhydrase-novel inhibitor interactions using surface plasmon resonance, isothermal titration calorimetry and fluorescence-based thermal shift assays.

This work describes the development of biophysical unbiased methods to study the interactions between new designed compounds and carbonic anhydrase II (CAII) enzyme. These methods have to permit both a screening of a series of sulfonamide derivatives and the identification of a lead compound after a thorough study of the most promising molecules. Interactions data were collected using surface plasmon resonance (SPR) and thermal shift assay (TSA).

New selective carbonic anhydrase IX inhibitors: synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides.

Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 4-(5-aryl-2-hydroxymethyl-pyrazol-1-yl)-benzenesulfonamides. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active site of hCA IX.

Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors.

In our continuing search for medicinal agents to treat proliferative diseases, quinazoline derivatives were synthesized and evaluated pharmacologically as epithelial growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitors. A quantitative structure-activity relationship analysis was conducted to rationalize the structure-activity relationship and to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be on the basis of the docking of lead coumpounds into the ATP-binding site. This model was used to direct the synthesis of new compounds.

Impact of aryloxy-linked quinazolines: a novel series of selective VEGFR-2 receptor tyrosine kinase inhibitors.

Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds have been evaluated for their enzymatic inhibition of VEGFR-2 and EGFR and for their antiproliferative activities on various cancer cell lines. We have studied the impact of the variation in the 4-position substitution of the quinazoline core.

Design, synthesis, and DNA-binding of N-alkyl(anilino)quinazoline derivatives.

New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and 13a-f), anilines (4a-m, 20a,b), N-alkyl(aniline) (5a-m, 21a,b, 22a,d), and N-aminoalkyl(aniline) (22e-g) have been synthesized. These molecules were evaluated for their cytotoxic activities and as potential DNA intercalating agents.

An objective method for bed capacity planning in a hospital department - a comparison with target ratio methods.

Objectives: To propose an objective approach in order to determine the number of beds required for a hospital department by considering how recruitment fluctuates over time. To compare this approach with classical bed capacity planning techniques.

Methods: A simulated data-based evaluation of the impact that the variability in hospital department activity produces upon the performance of methods used for determining the number of beds required.

[Central-venous-catheter-related bacteremia in neonatalogy].

Objective: The aim of this retrospective study was to identify the risk factors for catheter-associated bloodstream infection (CABSI) in neonates.

Method And Results: Fifteen episodes of CABSI occurred in 108 central catheters over a period of one year (2002). The univariate analysis risk factors were birth weight (1.

A simple method to optimize hospital beds capacity.

Objective: The number of acute hospital beds is determined by health authorities using methods based on ratios and/or target bed occupancy rates. These methods fail to consider the variability in hospitalization demands over time. On the other hand, the implementation of sophisticated models requires the decision concerning the number of beds to be made by an expert.

Why do we keep on meeting like this? The board as ritual in health and social care.

Despite their prevalence and longevity in many forms of social organization, most research on formal meetings suggests that they do not fulfil the instrumental purposes (e.g. setting strategy) that their constitutions propose.

Beds Simulator 1.0: a software for the modelisation of the number of beds required for a hospital department.

The determination of the number of beds needed for a hospital department is a complex problem that try to take into account efficiency, forecasting of needs, appropriateness of stays. Health authority used methods based on ratios that do not take into account local specificities and use rather to support an economic decision. On the other side, the models developed are too specific to be applied to all type of hospital department.

A universal method for determining intensive care unit bed requirements.

Objective: Most methods used to estimate ICU bed needs rely either on simple formulas that do not consider the actual needs of the population or on simulations that are too specific to be applicable to all hospitals. We sought to develop a universally applicable nonparametric method.

Design And Setting: For each day, the number of immediate patient transfers to other ICUs because of a full unit and the number of patients treated in the ICU were collected.

[Cause of non-pertinent hospital stays: interobserver concordance using the French version of the Appropriateness Evaluation Protocol].

Background: The modified French version of the Appropriateness Evaluation Protocol (AEPf) has been validated. Inappropriate days according to simple medical and technical criteria are identified with this tool. The aim of this study is to highlight the interest of investigating the reasons for inappropriate days and to assess the inter-observers reliability of the questionnaire developed for this purpose.

[Vitamin B12 deficiency in geriatrics].

Cobalamin deficiency increases with advancing age. The cut-off point of serum concentration should be raised, because many elderly people with "normal" serum vitamin B12 concentrations are metabolically deficient in cobalamin. The measurement of the metabolites homocysteine and/or methylmalonic acid is recommended.

[Reliability and validity of the French version of the first part of the Appropriateness Evaluation Protocol (AEPf): pertinent criteria of hospitalization stay].

Background: The Appropriateness Evaluation Protocol (AEP) is a tool used to identify hospitalization days that are appropriate with respect to simple technical criteria, and the reasons for hospitalization days that do not meet these criteria. The goal of the study was to validate the clinical criteria of AEPf, required for identifying the reasons which explain these inappropriate hospital days.

Methods: The validity of a French version of criteria of appropriateness (AEPf) was assessed in a sample of 502 hospital days in medical and surgical wards of six French teaching hospitals.

[Prolonged suppressive L-thyroxine therapy. Longitudinal study of the effect of LT4 on bone mineral density and bone metabolism markers in 71 patients].

Objectives: A prospective longitudinal study was conducted to investigate the influence of prolonged suppressive L-thyroxin therapy on bone density and biochemical markers of bone remodeling.

Patients And Methods: Seventy-one patients (including 28 menopaused women) taking long-term L-T4 for thyroid carcinoma were divided into 3 groups according to their TSH level: low (TSH < 0.04 mlU/l), moderate (0.

[Discharge from the geriatric clinic: factors predicting independent living at home].

This article presents the predictors for living at home 3 months, 6 months, 12 months, and 24 months after hospitalization in a geriatric clinic. The multivariate regression analysis revealed the predictive factors for living at home after 3 months: Incontinence, functional status judged by the physician, and balance performance. For living at home at 6 months, balance performance, handgrip were predictive, and at 12 months, balance performance, physicians judgement of functional abilities and Barthel-Index had the most predictive value.

[Epidemiology of falls and hip fractures].

The risk of falling increases with age and with many of the disorders common in late life. Approximately 35 to 40% of community-dwelling people over the age of 65 and up to 50% of institutionalized elderly fall at least once every year. The incidence is highest in women and the very old.