Quantitative structure-activity relationship to elucidate human CYP2A6 inhibition by organosulfur compounds

CYP2A6 is a human enzyme responsible for the metabolic elimination of nicotine, and it is also involved in the activation of procarcinogenic nitrosamines, especially those present in tobacco smoke. Several investigations have reported that reducing this enzyme activity may contribute to anti-smoking therapy as well as reducing the risk of promutagens in the body. For these reasons, several authors investigate selective inhibitors molecules toward this enzyme. The aim of this study was to evaluate the interactions between a set of organosulfur compounds and the CYP2A6 enzyme by a quantitative structure-activity relationship (QSAR) analysis. The present work provides a better understanding of the mechanisms involved, with the final goal of providing information for the future design of CYP2A6 inhibitors based on dietary compounds. The reported activity data were modeled by means of multiple regression analysis (MLR) and partial least-squares (PLS) techniques. The results indicate that hydrophobic and steric factors govern the union, while electronic factors are strongly involved in the case of monosulfides.Fil: Ramirez, Daniela Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; ArgentinaFil: Marchevsky, Eduardo Jorge. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Camargo, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; Argentin

QSAR studies on blood-brain barrier permeation

This review focuses on both physicochemical and theoretical QSAR methods for the prediction of drug transport across the blood-brain barrier (BBB). Special emphasis is given to the recent progress that has been made in the modeling of BBB penetration, with a particular focus on the models based on kinetic parameters of BBB permeability dataset. Physicochemical models based on partition coefficients and chromatographic capacity factors, as well as computerized parameters such as polar surface area and hydrogen-bonding descriptors are described and their success and limitations are discussed. Theoretical models based on topological or molecular orbital calculations are summarized and assessed in terms of descriptors, model type, predictive performance and interpretability. Strengths and weaknesses of the various methods are described. Related issues that are mentioned include the transporter-mediated permeation of drugs across the BBB and its implications on the stability and predictive quality of QSAR models.Fil: Luco, Juan Maria. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Laboratorio de Alimentos; ArgentinaFil: Marchevsky, Eduardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; Argentin

QSAR study for the soybean 15-lipoxygenase inhibitory activity of organosulfur compounds derived from the essential oil of garlic

In this study, multiple linear regression (MLR) and partial least-squares (PLS) techniques were used for modeling the soybean 15-lipoxygenase inhibitory activity of a varied group of mono-, di-, and trisulfides derived from the essential oil of garlic. The structures of the compounds under study were characterized by means of calculated physicochemical parameters and several nonempirical descriptors, such as topological, geometrical, and quantum chemical indices. The results obtained indicate that the inhibitory activity is strongly dependent on the ability of the compounds to participate in dispersive interactions with the enzyme, as expressed by the solvent-accessible surface area (SASA) and the average distance/distance degree descriptor (ADDD) index. On the other hand, the high contribution of the lowest unoccupied molecular orbit term (LUMO) in the PLS models derived for the di- and trisulfides suggests that the solute's electron-acceptor capacity plays a fundamental role in the inhibitory activity exhibited for these compounds. Finally, the geometric features as expressed by the shape parameters included in the models indicate a low but not negligible positive contribution of molecular linearity in the enzyme-inhibitor binding. In summary, the developed quantitative structure-activity relationship approach successfully accounts for the potencies of organosulfur compounds acting on soybean 15-lipoxygenase and thereby offers both a guide for the synthesis of new compounds and a hypothesis for the molecular basis of their activity.Fil: Camargo, Alejandra Beatriz. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Departamento de Ciencias Enológicas y Agroalimentarias. Laboratorio de Residuos Tóxicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marchevsky, Eduardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Laboratorio de Alimentos; Argentin

Estudio QSAR sobre la actividad antimicrobiana de chalconas sustituidas frente a cepas de Staphylococcus aureus resistente a meticilina usando técnicas cromatográficas y parámetros teóricos

El staphylococcus aureus resistente a la meticilina (comúnmente conocido como SARM) es causa frecuente de infecciones diversas, tanto de origen comunitario como hospitalario. El interés actual del estudio de este patógeno deriva, bien de su elevada frecuencia, o por representar una de las principales causas de graves brotes de infección nosocomial. Los flavonoides en general, las chalconas en particular, constituyen un grupo de particular interés debido principalmente a las múltiples propiedades biológicas que presentan tales compuestos1.En el presente trabajo, y considerando que nuestro grupo de trabajo estudia hace tiempo la acción antibacteriana de diversos flavonoides sobre microorganismos Gram positivos y Gram negativos, resultó interesante modelar mediante un estudio de QSAR la actividad bacteriostática ejercida sobre una cepa SARM (AM- 176) por una serie de 11 chalconas substituidas. Así, a partir de los datos de concentración inhibitoria mínima (CIM) obtenidos utilizando la técnica cinética turbidimétrica desarrollada previamente2, estos fueron correlacionados con parametros de retención cromatográficos (HPLC-IAM, membranas artificiales inmovilizadas) determinados experimentalmente en el presente trabajo y diversos descriptores moleculares utilizando la metodología de QSAR y técnicas de análisis multivariado tales como el análisis de mínimos cuadrados parciales (PLS). El modelo PLS desarrollado consistió en un modelo de dos componentes PLS y la estadística del modelo fue: R2 = 0,973 Q2 = 0,945 F = 142,79. Las siguientes figuras muestran las respectivas graficas de ?scores? y ?loadings?. En ellas se puede evidenciar el efecto de las variables sobre cada una de las chalconas en estudio.El modelo PLS obtenido fue validado por diversas ?data set? externas y por aplicación del test de permutación. El análisis del QSAR desarrollado pone en evidencia la importancia de los efectos hidrofobicos (MLOGP, TE1) y principalmente los factores geométricos (descriptores WHIM, E3e y De) en la acción bacteriostática ejercida por las chalconas bajo estudio.Fil: Talia, Juan Manuel. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ramirez, Daniela Andrea. Universidad Nacional de San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pereira, Sirley Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis; Argentina10º Congreso Argentino de Química AnalíticaLa PampaArgentinaAsociación Argentina de Químicos AnalíticosUniversidad Nacional de la Pampa. Facultad de Ciencias Exactas y Naturale

High-performance liquid chromatography of chalcones: Quantitative structure-retention relationships using partial least-squares (PLS) modeling

In this study, the multivariate partial least squares projections to latent structures (PLS) technique was used for modeling the RP-HPLC retention data of 17 chalcones, which were determined with methanol-water mobile phases of different compositions. The PLS model was based on molecular descriptors which can be calculated for any compound utilizing only the knowledge of its molecular structure. The PLS analysis resulted in a model with the following statistics: r = 0.976, Q = 0.933, s = 0.076, and F = 43.63. The adequacy of the developed model was assessed by means of cross-validation and also, by PLS modeling of the retention data of several chalcones reported by Walczak et al. [J. Chromatogr. 353, 123, (1986)], which were obtained using stationary phases of different polarity (-NH2, DIOL, -CN, ODS, C8). The structural interpretation of the developed PLS model was accomplished by means of comparative correlations between the nonempirical descriptors used in the model and the solvation parameters developed by Abraham. The results obtained in this work provides evidence for the great potential of the topological approach for the development of quantitative structure-retention relationship (QSRR) models.Fil: Montaña, Maria Paulina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química. Área de Química Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Pappano, Nora Beatriz. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química. Área de Química Física; ArgentinaFil: Debattista, Nora Beatriz. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química. Área de Química Física; ArgentinaFil: Raba, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química. Área de Química Física; ArgentinaFil: Luco, Juan Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Laboratorio de Alimentos; Argentin

Simultaneous spectrophotometric determination of rare-earth and transition elements using partial least-squares (PLS) multivariate calibration

A spectrophotometric method for the simultaneous determination of rare-earth and transition elements in synthetic superconductors, [(La1 – x Eu x )1.82Sr0.18CuO4], by the use of 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol (5-Br-PADAP) as chelating agent was developed. The influence of chemical variables affecting the reaction was studied. A partial least-squares (PLS) multivariate calibration procedure was used to assess the data obtained from several calibration solutions measured over the wavelengths range 400–700 nm. The concentration range for Cu was (1–12) × 10–6 mol/L, while the range for the rare-earth elements La and Eu was (2–8) × 10–6 mol/L. The relative errors in the determinations were less than 5% in most cases.Fil: Camiña, José Manuel. Universidad Nacional de La Pampa; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Ferreyra, Raquel Edith. Universidad Nacional de La Pampa; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis; ArgentinaFil: Marchevsky, Eduardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; Argentin

Simultaneous spectrophotometric determination of La, Ho, Mn 5-Br-PADAP complexes using multivariate calibration with partial least-squares (PLS) data evaluation

A simple and fast analytical pocedure is proposed for the simultaneous spectrophotometric determination of lanthanum, holmium and manganese in synthetic ceramics, (La(0.8-x) Hox Sr0.2 MnO3), by using the partial least-squares (PLS) method. As chromogenic agent 5-Br-PADAP [2-(5 -bromo-2-pyridylazo)-5 -diethylaminophenol] was used, which form colored complexes with the three elements studied. To avoid metal hydrolysis, a mixture of ethanol and Triton X-100 at pH 9.5 was used for all experiments. A set of 17 calibration solutions measured throughout the 400-700 nm wavelength range was used in the calibration step. The concentration range for Mn(II) was 1-12 × 10-6 mol L-1, while the range for the rare earth elements La(III) and Ho(III) was 2-8 × 10-6 mol L-1. In order to demonstrate the applicability of the proposed method, a set of artificial samples containing the three analytes in variable proportions was prepared and analyzed. The analytical results obtained were quite acceptable with relative errors not greater than 7% in most cases.Fil: Ferreyra, Raquel Edith. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Camiña, José Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Departamento de Química; ArgentinaFil: Marchevsky, Eduardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química. Área de Química Analítica; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Laboratorio de Alimentos; Argentin

Molecular Factors Influencing the Affinity of Flavonoid Compounds on PGlycoprotein Efflux Transporter

The most common mechanism of the so-called multidrug resistance (MDR), is mainly associated with an over expression of P-glycoprotein (Pgp). It is an ATP-dependent transport protein that limits the intracellular accumulation of a variety of structurally unrelated compounds within various organs and normal tissues such as kidney, small intestine and the blood brain barrier. Thus, the expression of Pgp has a major impact on the pharmacokinetic profile of many therapeutic agents and therefore, overcoming Pgp-mediated efflux constitutes an attractive means of potentially enhancing their therapeutic efficacy. The flavonoids comprise a large group of polyphenolic compounds that occur in plants and vegetables, and they have been shown to display a wide variety of biological activities. For example, anti-inflammatory, antioxidant, ntiallergic, hepatoprotective, antithrombotic, antiviral, and anticarcinogenic activities. The interactions between flavonoids and Pgp have also been extensively studied and some quantitative structure-activity relationships (QSAR) have been reported. In the present work, we have employed 2D-QSAR analysis to evaluate the interactions between Pgp and several flavonoid compounds with the aim of dentifying the molecular factors responsible for the Pgp-binding affinity evidenced by these compounds. Thus, the reported data for dissociation constants (KD) between Pgp and 62 flavonoid compounds were modeled by mean of multiple regression analysis (MLR), and structures of the compounds under study were characterized by means of calculated physicochemical properties and several topological and constitutional descriptors, as well as geometrical and quantum chemical indexes. The obtained results suggest that the hydrophobic and especially geometric factors are of prime importance for binding, whereas in the case of flavonoid derivatives with flavone (flavonols), flavanone and isoflavone nuclei, the electronic factors are also involved in electron donor/acceptor interactions. In addition, in the case of chalcones, the results suggest that the affinity toward P-gp of such compounds is mainly governed by intermolecular dispersive interactions at the binding site.Fil: Vázquez, Rodolfo Nieto. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Camargo, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; ArgentinaFil: Marchevsky, Eduardo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentin

Solid phase microextraction coupled to liquid chromatography: Analysis of organosulfur compounds avoiding artifacts formation

This work proposes the novel application of a microextraction technique, solid phase microextraction (SPME), coupled to liquid chromatography with UV detection (HPLC?UV) for the analysis of organosulfur compounds (OSCs) in garlic samples. Additionally, a comparative study of OSCs profiles obtained by SPME coupled to HPLC?UV and gas chromatography with flame photometric detector (GC?FPD), respectively; was carried out. This study provided complementary evidence about OSCs?s lability and ??artifacts?? formation during the analytical process. Raw, cooked and distilled garlic samples were considered. The target analytes were diallyl disulphide (DADS), diallyl sulphide (DAS), diallyl trisulphide (DATS), allicin, 3-vinyl- 4H-1,3-dithiin (3-VD), 2-vinyl-4H-1,2-dithiin (2-VD) and (E)- and (Z)-ajoene, which are the most important OSCs with biological activities present in raw and processed garlic. The coupling of SPME and HPLC showed to be reliable, fast, sensible and selective methodology for OSCs analysis.Fil: Locatelli, Daniela Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; ArgentinaFil: Altamirano, Jorgelina Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Luco, Juan Maria. Universidad Nacional de San Luis. Facultad de Química Bioquímica y Farmacia, ; ArgentinaFil: Norlin, Rikard. Swedish defence research agency; SueciaFil: Camargo, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; Argentin

Permeability data of organosulfur garlic compounds estimated by immobilized artificial membrane chromatography: correlation across several biological barriers

Among healthy vegetables, those of the genus Allium stand out. Antioxidant and anti-inflammatory properties have been associated with these vegetables, attributed mainly to organosulfur compounds (OSCs). In turn, they are linked to a protective effect counteracting cardiovascular disease development. Now, to really ensure the bioactive efficacy of the said compounds once consumed, it is necessary to previously evaluate the ADME (absorption, distribution, metabolism, and excretion) profile. Alternatively, in vitro and in silico methods attempt to avoid or reduce experimental animals’ use and provide preliminary information on drugs’ ability to overcome the various biological barriers inherent in the ADME process. In this sense, in silico methods serve to provide primary information on drugs’ bioavailability mechanisms. High-performance liquid chromatography (HPLC) using a stationary phase composed of phospholipids, the so-called immobilized artificial membrane (IAM), has been widely recognized as a valuable alternative method to extract and quantify information about the structure and physicochemical properties of organic compounds which are extensively used in studies of quantitative structure–activity relationships (QSARs). In the present study, the chromatographic capacity factors (log k’ (IAM)) for 28 OSCs were determined by IAM-HPLC. In order to evaluate the ability of the IAM phase in assessing lipophilicity of the compounds under study, several quantitative structure–retention relationships (QSRRs) were derived from exploring fundamental intermolecular interactions that govern the retention of compounds under study on IAM phases. As expected, the hydrophobic factors are of prime importance for the IAM retention of these compounds. However, the molecular flexibility and specific polar interactions expressed by several electronic descriptors (relative negative charge, RNCG, and Mulliken electronegativity) are also involved. We also evaluated the IAM phase ability to assess several ADME parameters for the OSCs under study obtained using the SwissADME web tool integrated into the SwissDrugDesign workspace and the PreADMET web tool. The human gastrointestinal absorption (HIA), blood–brain barrier (BBB) permeation, and skin permeability were investigated through QSAR modeling, using several chemometric approaches. The ADME properties under study are strongly dependent on hydrophobic factors as expressed by log k’(IAM), which provide evidence for the great potential of the IAM phases in the development of QSAR models.Fil: Ramirez, Daniela Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; ArgentinaFil: Federici, Maria Fernanda. Universidad Nacional de Cuyo; ArgentinaFil: Altamirano, Jorgelina Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla | Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla | Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Museo de Historia Natural de San Rafael - Ianigla; ArgentinaFil: Camargo, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; ArgentinaFil: Luco, Juan María. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentin