5,6-dihydro-2H-pyranones and 5,6-dihydro-2H-pyridones and their derivatives modulate in vitro human T lymphocyte function.

The aim of this work was to study the in vitro effects of δ-lactone 1, δ-lactam 3 and their enaminone derivatives 2 and 4, synthesized in our laboratory, on the proliferative responses of human lymphocytes, Th1 and Th2 cytokine secretion and intracellular redox status. Peripheral blood lymphocytes were isolated using differential centrifugation on a density gradient of Histopaque. They were cultured with mitogen concanavalin A (Con A) and with different concentrations of the compounds 1, 2, 3 and 4 (0.1-10 µM). Proliferation (MTT assay), IL-2, INFγ and IL-4 (Elisa kits), oxidative markers (intracellular glutathione, hydroperoxide and carbonyl protein contents) and cytotoxic effect (micronucleus test) were determined. The compounds 1 and 2 are immunosuppressive and decrease IL-2, INFγ and IL-4 secretion with a shift away from Th2 response to Th1 phenotype. The compounds 3 and 4 were immunostimulant and increased cytokine secretion with a shift away from Th1 response to Th2. The introduction of an enamine group to 1 and 3 to provide 2 and 4 seemed to attenuate their immunological properties. These immunomodulatory properties were, however, accompanied by an increase in lymphocyte intracellular oxidative stress, especially with 1 and 2 at high concentrations. In conclusion, the compounds 1, 2, 3 and 4 could be used to provide cell-mediated immune responses for novel therapies in T-cell mediated immune disorders.

New ionic liquid for inorganic cations analysis by capillary electrophoresis: 2-hydroxy-N,N,N-trimethyl-1-phenylethanaminium bis(trifluoromethylsulfonyl)imide (phenylcholine NTf2).

The potentialities of new ionic liquids (ILs) based on choline were evaluated as an electrophoretic medium in capillary electrophoresis for the analysis of alkaline and alkaline earth cations (Li(+), K(+), Na(+), Cs(+), Mg(2+), Ba(2+), Ca(2+), and Sr(2+)) with indirect UV detection. Two types of capillaries were tested: an untreated fused silica and fused silica coated with a film of polyvinylalcohol. The coated capillary proved to be the best adapted for the metal ions studied. Moreover, it appeared that the nature of the ionic liquid anion influenced the baseline stability, and the bis(trifluoromethylsulfonyl) imide (NTf(2) (-)) anion seemed to be the most efficient. These preliminary studies led us to synthesize a new ionic liquid, 2-hydroxy-N,N,N-trimethyl-1-phenylethanaminium NTf(2) (phenylcholine NTf(2)). This liquid was able to act as the running electrolyte and probe, generating the background signal in indirect UV light and consequently simplifying the electrophoretic medium. Excellent baseline stability, good reproducibility, as well as good sensitivity of detection were obtained with this new ionic liquid. Thus, 510,000 plates/meter for Li(+) with 40 mM IL were successfully obtained. The optimal concentration of IL was 20 mM with a detection limit ranging from 28 microg L(-1) for Li(+) to 1,000 microg L(-1) for Cs(+). This method (phenylcholine NTf(2) with polyvinylalcohol capillary) was applied to analyze different commercial source and mineral waters. Finally, the potentiality of this ionic liquid in nonaqueous capillary electrophoresis was explored. The use of phenylcholine NTf(2) with a fused silica capillary, in pure methanol medium and in the presence of acetic acid, made it possible to obtain separation selectivity different from that obtained in aqueous medium.

A new example of reversal of the order of migration of enantiomers, as a function of cyclodextrin concentration and pH, by cyclodextrin-modified capillary zone electrophoresis: enantioseparation of 6,6'-dibromo-1,1'-binaphthyl-2,2'-diol.

Enantioseparation of 6,6'-dibromo-1,1'-binaphthyl-2,2'-diol (DBBD) by cyclodextrin-modified capillary zone electrophoresis (CD-CZE) was studied using the three native alpha, beta, and gamma cyclodextrins, the three hydroxypropylated cyclodextrins (2-hydroxypropyl-alpha, beta, and gamma), heptakis-2,6-di-O-methyl-beta-CD (DM-beta-CD), and heptakis-2,3,6-tri-O-methyl-beta-cyclodextrin (TM-beta-CD). First, the acidity constants of DBBD were determined using capillary electrophoresis, before performing enantioseparation. The influence of the concentrations of the studied cyclodextrins on the enantioseparation was explored and the experimental optimal concentrations were determined and compared to the theoretical optimal concentrations. Moreover, the apparent complexation constants between each studied cyclodextrin and the two DBBD enantiomers were evaluated using a non-linear curve fitting method and three linear plotting methods (x-reciprocal, y-reciprocal and double reciprocal). For TM-beta-CD, the order of migration of the enantiomers of DBBD reversed as a function of TM-beta-CD concentration. The influence of the nature of methylated cyclodextrin derivatives (methyl-beta-CD (M-beta-CD) and DM-beta-CD) was then studied. Inversion of the order of migration of the enantiomers of DBBD was observed for DM-beta-CD, whereas the S enantiomer of DBBD always migrated first for M-beta-CD.

Enantioseparation of binaphthol and its mono derivatives by cyclodextrin-modified capillary zone electrophoresis.

Chiral binaphthols belong to the group of most effective ligands for asymmetrical catalysis. In this context, various binaphthols presenting original substituents have been synthesized. Their study through capillary electrophoresis is the object of this work. The literature dedicated to the separation of atropisomers by capillary electrophoresis, corresponding only to binaphthol, reveals that its enantioseparation is always delicate because of the influence of many factors and the resolutions obtained are weak. Therefore, for a structured optimization, we first successfully evaluated the acidity constants of different binaphthols by means of capillary electrophoresis. With these known physicochemical characteristics, we could successfully carry out enantiomeric separations of the different binaphthols at pH 11.5, practically in completely ionized form, in phosphate medium, and in the presence of cyclodextrin (CD), with analysis times lower than 8min. The nature of CDs (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD), HP-beta-CD, HP-gamma-CD and trimethyl-beta-CD (TM-beta-CD)) and other factors in relation to enantiomeric resolution (applied voltage, nature and concentration of the electrolyte, and concentration of cyclodextrin) were optimized. These studies allowed us to determine the optimal conditions of separation (concentration and nature of CD) for each of the studied binaphthols. It is necessary to mention that, for the 1,1'-binaphthyl-2,2'-diol (Binol) at pH 11.5, the S atropisomer always migrated first, regardless of the nature and concentration of the cyclodextrin used. Moreover, an inversion in elution order of the two atropisomers as a function of pH was observed with gamma-CD (pH range: 10-11.5). The R atropisomer migrated first at pH 10. At pH 10.8 the migration order of the two atropisomers of Binol was reversed as a function of gamma-CD concentration. Finally, the addition of chiral ionic liquids (R(-)-1-hydroxy-N,N,N-trimethylbutan-2-aminium bis(trifluoromethylsulfonyl)imide and S(+)-tetrabutylammonium camphorsulfonate) was conducted. In the case of S(+)-tetrabutylammonium camphorsulfonate, a weak antagonistic effect was observed with modeling the evolution of enantiomeric resolution by means of the experimental design, while in the case of R(-)-1-hydroxy-N,N,N-trimethylbutan-2-aminium bis(trifluoromethylsulfonyl)imide the effect was neutral.

Comparative QSAR based on neural networks for the anti-HIV activity of HEPT derivatives.

Among the non-nucleoside reverse transcriptase inhibitors, 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine (HEPT) derivatives have proved to be potent and selective inhibitors of human immunodeficiency virus (HIV-1). They are able to completely suppress virus replication in cell cultures. The quantitative structure-activity relationships (QSAR) try to describe the association between biological activities of a group of congeners and their molecular descriptors. In this paper, recent works on the application of neural networks (NN) and multiple regression analyses to quantitative structure-anti-HIV activity of HEPT derivatives are reviewed. NN have their origins in efforts to reproduce computer models of the information processing that takes place in the brain. They have found application in a wide variety of fields, such as image analysis of facial features, stock market predictions, etc. Application of the NN methods to problems in chemistry and biochemistry has rapidly gained popularity in recent years. We briefly describe a methodology for designing NN for QSAR and estimating their performances, and apply this approach to the prediction of anti-HIV activity of HEPT. The predictive power of the NN used is compared with that of other statistical methods.

A one step process for grafting organic pendants on alumina via the reaction of alumina and phosphonate under microwave irradiation.

Phosphonate esters react with gamma-alumina under microwave (MW) irradiation; this reaction is a simple preparative method to graft organic pendant groups onto the surface of alumina; the efficiency of the grafting was readily checked by solid-state NMR techniques (31P and 27Al).

Neural networks studies: quantitative structure-activity relationships of antifungal 1.

Models of relationships between structure and antifungal activity of 1-[2-(substituted phenyl)allyl]imidazoles and related compounds were constructed by means of a multilayer neural network using the back-propagation (BP) algorithm. Each molecule was described by three structural and one physicochemical parameters. The leave-one-out procedure was used to assess the predictive ability of a neural network model. The results obtained were compared to those given in the literature by the multiple linear regression (MLR), and were found to be better. The contribution of each descriptor to the structure-activity relationships was evaluated. Hydrophobicity of the molecule was confirmed to take the most relevant part in the molecular description.

Antibacterial and antifungal activity of lawsone and novel naphthoquinone derivatives.

INTRODUCTION: Naphthoquinone derivatives are under investigation as potential therapeutic agents. The antibacterial and antifungal activity of lawsone and of some novel naphthoquinone derivatives was assessed in vitro. METHODS: The antimicrobial activity was determined using diffusion disk and the broth microdilution methods against seven bacteria and three Candida species, according to recommendations of the Clinical and Laboratory Standards Institute. RESULTS: Two compounds (P05 et P06) presented a good antibacterial effectiveness against two gram-positive bacteria. No antifungal potency was observed against the three Candida albicans strains used in the test. CONCLUSION: Our results prove that the introduction of substituents on ketone function position 4 decreased the antimicrobial properties of the synthetized compounds.

Quantitative structure-activity relationship studies of TIBO derivatives using support vector machines.

A quantitative structure-activity relationship (QSAR) study is suggested for the prediction of anti-HIV activity of tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepinone (TIBO) derivatives. The model was produced by using the support vector machine (SVM) technique to develop quantitative relationships between the anti-HIV activity and ten molecular descriptors of 89 TIBO derivatives. The performance and predictive capability of the SVM method were investigated and compared with other techniques such as artificial neural networks and multiple linear regression. The results obtained indicate that the SVM model with the kernel radial basis function can be successfully used to predict the anti-HIV activity of TIBO derivatives with only ten molecular descriptors that can be calculated directly from only molecular structure. The contribution of each descriptor to the structure-activity relationships was evaluated. Hydrophobicity of the molecule was thus found to take the most relevant part in the molecular description.

Enantioseparation of binaphthol and its monoderivatives by cyclodextrin-modified capillary zone electrophoresis: a mathematical approach.

A simple model for the separation of atropisomers of binaphthol and its monoderivatives by means of cyclodextrin-modified capillary zone electrophoresis (CD-CZE) was used to describe the migration behavior of poly charged enantiomers in a chiral separation system. This mathematical approach allowed for the determination of the optimal cyclodextrin concentrations for the enantioseparation of binaphthols by taking into account the influence of the formed complex mobilities. Moreover, using this theoretical approach, the reversal of the enantiomers' migration order as a function of cyclodextrin concentration was predicated. The apparent complexation constants between the cyclodextrins and the binaphthol and its monoderivatives could be calculated using a non-linear curve fitting method and three linear plotting methods (x-reciprocal, y-reciprocal and double reciprocal). Good agreements between the theoretical and experimental cyclodextrin concentrations were obtained.

Determination of acidity constants of enolisable compounds by capillary electrophoresis.

Research on the structure-activity relationships of molecules with acidic carbon atoms led us to undertake a feasibility study on the determination of their acidity constants by capillary electrophoresis (CE). The studied molecules had diverse structures and were tetronic acid, acetylacetone, diethylmalonate, Meldrum's acid, 3-methylrhodanine, nitroacetic acid ethyl ester, pyrimidine-2,4,6-trione, 3-oxo-3-phenylpropionic acid ethyl ester, 1-phenylbutan-1,3-dione, 5,5-dimethylcyclohexan-1,3-dione and homophthalic anhydride. The p Ka range explored by CE was therefore very large (from 3 to 12) and p Ka values near 12 were evaluated by mathematical extrapolations. The analyses were carried out in CZE mode using a fused silica capillary grafted (or not) with hexadimethrine. Owing to the electrophoretic behaviour of these compounds according to the pH, their acidity constants could be evaluated and appeared in perfect agreement with the literature data obtained, a few decades ago, by means of potentiometry, spectrometry or conductimetry. The p Ka of homophthalic anhydride and 3-methylrhodanine were evaluated for the first time.

[Value and limits of estrioluria in cases of retarded fetal growth]. / Valeur et limites de l'oestriolurie dans les retards de croissance du foetus.

On the basis of personal experience of 56 cases of retarded intra-uterine growth (RIUG) followed during the course of pregnancy by means of repeated estriol determinations (213 values), the authors note that : In 2/3 of the cases the urinary estriol level was higher than the lower limit of normality. The urinary estriol levels were not related to the severity of the RIUG. The estriol level has a limited value in the diagnosis of RIUG. The authors emphasize the prognostic value of the curves of estrioluria in this pathology and propose a course of obstetrical management based on interpretation of the curves.