In silico evaluation of new mangiferin-based Positron Emission Tomography radiopharmaceuticals through the inhibition of metalloproteinase-9.

Metalloproteinase-9 (MMP-9) is a key protein in cancer advancement and metastasis owing to its ability to degrade some extracellular matrix components. Mangiferin, a natural polyphenolic compound, has demonstrated through experimental and theoretical studies to be a great anticancer agent for the selective inhibition of MMP-9. This work aimed to evaluate the utility of several fluorinated compounds obtained from MF as possible Positron Emission Tomography (PET) radiopharmaceuticals oriented to MMP-9. Density Functional Theory calculations of MF were made to obtain the most active sites toward electrophilic and nucleophilic reactions and propose a synthetic route to produce its fluorinated derivatives. The reactivity study allowed us to propose a late-stage synthetic route based on click chemistry to obtain three fluorinated MF-based derivatives. Molecular docking calculations suggested that the derivative F-propyl-MF could be suitable as PET radiopharmaceutical owing to the establishment of a five-coordinated complex with the catalytic Zn atom belonging to the active site of MMP-9, crucial factor in the inhibition of MMP-9.

Competitive formation of molecular inclusion complexes of chlordecone and ß-hexachlorocyclohexane with natural cyclodextrins: DFT and molecular dynamics study.

CONTEXT: Chlordecone (CLD) and ß-hexachlorocyclohexane (ß-HCH) are chlorinated pesticides that coexist as persistent organic pollutants in the groundwater of several countries in the Caribbean, being an environmental issue. This work evaluates theoretically the competitive formation of host-guest complexes pesticides@cyclodextrines (CDs) as an alternative for water purification and selective separation of pesticides. METHODS: Quantum mechanical calculations based on density functional theory (DFT) and classical molecular dynamics (MD) simulations were used to achieve information on geometries, energies, structure, and dynamics of guest-host complexes in the gas phase, implicit solvent medium, and in aqueous solutions. RESULTS: DFT studies showed that interactions of both pesticides with CDs are mediated by steric factors and guided by maximization of the hydrophobic interactions either with the other pesticide or with the CD cavity's inner atoms. MD results corroborate the formation of stable complexes of both pesticides with the studied CDs. α-CD exhibited a preference for the smaller ß-HCH molecule over the CLD that could not perturb the formed complex. CONCLUSIONS: The simulation of competitive formation with γ-CD illustrated that this molecule could accommodate both pesticides inside its cavity. These results suggest that CDs with smaller cavity sizes such as α-CD could be used for selective separation of ß-HCH from CLD in water bodies, while γ-CD could be used for methods that aim to remove both pesticides at the same time.

Adsorption of Hexavalent Chromium Using Activated Carbon Produced from Sargassum ssp.: Comparison between Lab Experiments and Molecular Dynamics Simulations.

Adsorption is one of the most successful physicochemical approaches for removing heavy metal contaminants from polluted water. The use of residual biomass for the production of adsorbents has attracted a lot of attention due to its cheap price and environmentally friendly approach. The transformation of Sargassum-an invasive brown macroalga-into activated carbon (AC) via phosphoric acid thermochemical activation was explored in an effort to increase the value of Sargassum seaweed biomass. Several techniques (nitrogen adsorption, pHPZC, Boehm titration, FTIR and XPS) were used to characterize the physicochemical properties of the activated carbons. The SAC600 3/1 was predominantly microporous and mesoporous (39.6% and 60.4%, respectively) and revealed a high specific surface area (1695 m2·g-1). To serve as a comparison element, a commercial reference activated carbon with a large specific surface area (1900 m2·g-1) was also investigated. The influence of several parameters on the adsorption capacity of AC was studied: solution pH, solution temperature, contact time and Cr(VI) concentration. The best adsorption capacities were found at very acid (pH 2) solution pH and at lower temperatures. The adsorption kinetics of SAC600 3/1 fitted well a pseudo-second-order type 1 model and the adsorption isotherm was better described by a Jovanovic-Freundlich isotherm model. Molecular dynamics (MD) simulations confirmed the experimental results and determined that hydroxyl and carboxylate groups are the most influential functional groups in the adsorption process of chromium anions. MD simulations also showed that the addition of MgCl2 to the activated carbon surface before adsorption experiments, slightly increases the adsorption of HCrO4- and CrO42- anions. Finally, this theoretical study was experimentally validated obtaining an increase of 5.6% in chromium uptake.

Explaining the interaction of mangiferin with MMP-9 and NF-ƙß: a computational study.

Mangiferin is a glycosylated xanthone widely distributed in nature, which exhibits wide pharmacological activities, highlighting its anti-cancer properties. Mangiferin interferes with inflammation, lipid, and calcium signaling, which selectively inhibits multiple NFkB target genes as interleukin-6, tumor necrosis factor, plasminogen, and matrix metalloproteinase, among others. In this work, the interactions of this polyphenol with MMP-9 and NF-κß are characterized by using computational chemistry methods. The results show MMP-9 inhibition by mangiferina is characterized for the interact with the catalytic Zn atom through a penta-coordinate structure. It is also demonstrated through a strong charge transfer established between mangiferin and Zn in the QM/MM study. Concerning the mangiferin/NF-κß system, the 92.3% of interactions between p50 sub-unity and DNA are maintained with a binding energy of - 8.04 kcal/mol. These findings indicate that mangiferin blocks the p50-p65/DNA interaction resulting in the loss of the functions of this hetero-dimeric member and suggesting inhibition of the cancer progression. Experimental results concerning the anti-cancer properties of mangiferin show that this natural compound can inhibit selectively MMP-9 and NF-ƙß. Although the anti-tumor properties of mangiferin are well defined, its molecular mechanisms of actions are not described. In this work, a computational study is carried out to characterize the interactions of mangiferin with these molecular targets. The results obtained corroborate the anti-proliferative and anti-apoptotic activity of mangiferin and provide a depiction of its mechanisms of action.

In silico development of new PET radiopharmaceuticals from mTOR inhibitors.

Rapamycin (or sirolimus) is a macrolide that has shown to be useful as an immunosuppressant and that was studied in metabolic, neurological, or genetic disorders. Rapamycin is a specific natural inhibitor of the mechanistic target of rapamycin (mTOR) that is a kinase protein playing a pivotal role in cell growth and proliferation by activation of several metabolic processes. This work aimed to evaluate the utility of several compounds obtained from rapamycin and its semi-synthetic analogs everolimus and temsirolimus as possible radiopharmaceuticals oriented to this protein. Density Functional Theory calculations of these molecules were made and further analysis of the dual descriptor, charges populations, and of the electrostatic potential surfaces were performed. Molecular docking simulations were used to evaluate the interactions of the rapamycin with the studied candidates. They allowed us to propose two strategies for the synthesis of novel compounds based on electrophilic reactions. Molecular docking results also helped us to eliminate molecules that did not interact correctly with the target. Finally, we found for the first time, that the novel compounds synthesized through the electrophilic addition reaction that employed 18F-selectfluor, should maintain the biological activity of original compounds and could be suitable as Positron Emission Tomography radiopharmaceuticals targeting mTOR Complex1 system.

Role of Basic Surface Groups of Activated Carbon in Chlordecone and ß-Hexachlorocyclohexane Adsorption: A Molecular Modelling Study.

The influence of nitrogen-containing surface groups (SGs) onto activated carbon (AC) over the adsorption of chlordecone (CLD) and ß-hexachlorocyclohexane (ß-HCH) was characterized by a molecular modelling study, considering pH (single protonated SGs) and hydration effect (up to three water molecules). The interactions of both pollutants with amines and pyridine as basic SGs of AC were studied, applying the multiple minima hypersurface (MMH) methodology and using PM7 semiempirical Hamiltonian. Representative structures from MMH were reoptimized using the M06-2X density functional theory. The quantum theory of atoms in molecules (QTAIM) was used to characterize the interaction types in order understanding the adsorption process. A favorable association of both pesticides with the amines and pyridine SGs onto AC was observed at all pH ranges, both in the absence and presence of water molecules. However, a greater association of both pollutants with the primary amine was found under an acidic pH condition. QTAIM results show that the interactions of CLD and ß-HCH with the SGs onto AC are governed by Cl···C interactions of chlorine atoms of both pesticides with the graphitic surface. Electrostatic interactions (H-bonds) were observed when water molecules were added to the systems. A physisorption mechanism is suggested for CLD and ß-HCH adsorption on nitrogen-containing SGs of AC.

Enhancement of ciprofloxacin degradation in aqueous system by heterogeneous catalytic ozonation.

Fluoroquinolones are extensively used in medicine due to their antimicrobial activity. Their presence in water inhibits microorganism activity in conventional wastewater treatment plants. This study aims to evaluate the technical feasibility of applying heterogeneous catalytic ozonation to eliminate ciprofloxacin (CIP) as a representative of fluoroquinolone antibiotics normally present in municipal wastewater discharges. Experiments were conducted in a semi-batch stirred slurry reactor, using 0.7 L of 100 mg L-1 CIP aqueous solution, at pH 3 and 30 °C. Experimental results show that single ozonation can easily oxidise CIP molecules (68%) within the first 5 min, leading to the generation of refractory oxidation by-products. However, when heterogeneous catalytic ozonation is applied using iron oxide supported on MFI synthetic zeolite, total degradation of CIP is observed at 5 min and a higher mineralisation rate is obtained. A novel sequential process is developed for CIP mineralisation. In a first step, a flash single ozonation is applied and CIP molecules are broken down. Then, a catalytic ozonation step is conducted by adding the Fe/MFI catalyst into the reactor. As a result of catalyst addition, 44% of Total Organic Carbon (TOC) is eliminated within the first 15 min, compared to single ozonation where only 13% of TOC removal is reached in the same time. The application of this sequential process to a real wastewater effluent spiked with CIP leads to 52% of TOC removal.

Evaluation of the molecular inclusion process of ß-hexachlorocyclohexane in cyclodextrins.

The present work aimed to study the guest-host complexes of ß-hexachlorocyclohexane (ß-HCH), a pesticide with high environmental stability that can cause severe health problems, with the most common cyclodextrins (α-, ß-, and γ-CDs). The formation reactions of these molecular inclusion complexes were addressed in this research. The multiple minima hypersurface methodology, quantum calculations based on density functional theory and a topological exploration of the electron density based on the quantum theory of atoms in molecules approach were used to characterize the interaction spaces of the pollutant with the three CDs. Additionally, charge distribution, charge transfer and dual descriptor analyses were employed to elucidate the driving forces involved in the formation of these molecular inclusion complexes. Three types of fundamental interactions were observed: total occlusion, partial occlusion and external interaction (non-occlusion). Finally, experiments were performed to confirm the formation of the studied complexes. The most stable complexes were obtained when γ-CD was the host molecule. The interactions between the pesticide and CDs have fundamentally dispersive natures, as was confirmed experimentally by spectroscopic results. All the obtained results suggest the possibility of using CDs for the purification and treatment of water polluted with ß-HCH.

Degradation of chlordecone and beta-hexachlorocyclohexane by photolysis, (photo-)fenton oxidation and ozonation.

Intensive use of chlorinated pesticides from the 1960s to the 1990s has resulted in a diffuse contamination of soils and surface waters in the banana-producing areas of the French West Indies. The purpose of this research was, for the first time, to examine the degradation of two of these persistent pollutants - chlordecone (CLD) and beta-hexachlorocyclohexane (ß-HCH) in 1 mg L-1 synthetic aqueous solutions by means of photolysis, (photo-) Fenton oxidation and ozonation processes. Fenton oxidation is not efficient for CLD and yields less than 15% reduction of ß-HCH concentration in 5 h. Conversely, both molecules can be quantitatively converted under UV-Vis irradiation reaching 100% of degradation in 5 h, while combination with hydrogen peroxide and ferrous iron does not show any significant improvement except in high wavelength range (>280 nm). Ozonation exhibits comparable but lower degradation rates than UV processes. Preliminary identification of degradation products indicated that hydrochlordecone was formed during photo-Fenton oxidation of CLD, while for ß-HCH the major product peak exhibited C3H3Cl2 as most abundant fragment.

Improving degradation of paracetamol by integrating gamma radiation and Fenton processes.

Degradation of paracetamol (N-(4-hydroxiphenyl)acetamide) in aqueous solution by gamma radiation, gamma radiation/H2O2 and gamma radiation/Fenton processes was studied. Parameters affecting the radiolysis of paracetamol such as radiation dose, initial concentration of pollutant, pH and initial oxidant concentration were investigated. Gamma radiation was performed using a (60)Co source irradiator. Paracetamol degradation and mineralization increased with increasing absorbed radiation dose, but decreased with increasing initial concentration of the drug in aqueous solution. The addition of H2O2 resulted in an increased effect on irradiation-driven paracetamol degradation in comparison with the performance of the irradiation-driven process alone: paracetamol removal increased from 48.9% in the absence of H2O2 to 95.2% for H2O2 concentration of 41.7 mmol/L. However, the best results were obtained with gamma radiation/Fenton process with 100% of the drug removal at 5 kGy, for optimal H2O2 and Fe(2+) concentrations at 13.9 and 2.3 mmol/L, respectively, with a high mineralization of 63.7%. These results suggest gamma radiation/H2O2 and gamma radiation/Fenton processes as promising methods for paracetamol degradation in polluted wastewaters.

Situación y perspectivas para el desarrollo de materiales de referencia para la Industria Farmacéutica cubana / State and perspectives for reference material for Cuban Pharmaceutical Industry

La necesidad de contar con mediciones exactas es una premisa fundamental del desarrollo científico, tecnológico, económico y comercial de la sociedad moderna. La calidad de las mediciones químicas, físicas y biológicas pueden ser aseguradas mediante el uso de materiales de referencia (MR) fiables. En el caso de la industria farmacéutica, los MR son imprescindibles en el control de la calidad y aseguramiento de sus producciones; constituyen medios para evaluar cuantitativa y cualitativamente diferentes características de la composición de los ingredientes activos, los compuestos relacionados, los productos de degradación, las materias primas y las formas farmacéuticas, y establecen la trazabilidad del resultado obtenido o la asignación del valor de la muestra de ensayo. Además, su empleo es una herramienta esencial en el establecimiento de los sistemas de Gestión de la Calidad; para la evaluación de la conformidad y para la acreditación de laboratorios de ensayos, lo cual ha generado un incremento considerable en su demanda....

Improved model of multicomponent adsorption in reversed-phase liquid chromatography.

This work presents a modification to the real adsorbed solution model using a Flory-Huggins type of expression that was reported previously. This modification consists in replacing the Flory-Huggins activity coefficient by the spreading pressure dependent approach. This new model takes into account explicitly the adsorbate-adsorbate interactions taking place in the adsorbed phase. It provides an excellent prediction of the competitive, ternary adsorption equilibrium of benzyl alcohol, 2-phenylethanol and 2-methyl benzyl alcohol observed in a reversed-phase liquid chromatographic system using information merely derived from the single-component adsorption experimental data.