Uudsete heterotsükliliste hüdrasiini derivaatide ja nende konjugaatide süntees

Väitekirja elektrooniline versioon ei sisalda publikatsiooneHüdrasiin on lihtne keemiline ühend molekulvalemiga N2H4. Ilmselt teatakse seda kõige paremini filmist „Marslane“ (2015), milles astronaut Mark Watney (Matt Damon) kasutas võõral planeedil ellujäämiseks seda algselt raketikütusena kasutatavat ühendit, et lagundada see vesinikuks, millest seejärel valmistada vett. Hüdrasiin on iseenesest väga mürgine, kuid selle derivaate on eraldatud mitmetest elusorganismidest. Need derivaadid on tihti selektiivse toksilisusega kas viiruste, bakterite, seente või vähirakkude vastu. Selektiivsel toksilisusel põhineb paljude ravimite toime, mistõttu on need ühendid äratanud ka ravimiarendajate huvi. Heterotsüklilisteks nimetatakse keemilisi ühendeid, mis sisaldavad tsüklilist struktuurielementi ning mis omakorda koosneb vähemalt kahte eri tüüpi aatomitest. Heterotsüklilistel ühenditel on suur roll farmaatsiatööstuses, kuna enamus ravimeid on heterotsüklilised ning 90% nendest heterotsüklitest sisaldab lämmastiku aatomit. Näiteks 2012. aastal võis heterotsükleid leida kõigist kümnest enimmüüdud ravimist, millest 8 sisaldas seejuures ka lämmastiku aatomit. Sünteesimeetodid, mille abil saab sünteesida heterotsüklilisi ühendeid, mis sisaldavad ühtlasi ka lämmastik-lämmastik sidet olles seega samaaegselt ka hüdrasiini derivaadid, on üsna vähetuntud. Seetõttu oli antud doktoritöö eesmärk laiendada sünteetilisi võimalusi selliste uudsete ja perspektiivsete ühendite valmistamiseks.Hydrazine, a simple compound with a molecular formula N2H4 is probably most well-known from the movie „The Martian“ (2015). Hydrazine – originally used as a rocket fuel – was decomposed to hydrogen, which was then oxidized to water by fictional astronaut Mark Watney (Matt Damon) to survive on a foreign planet. Hydrazine itself is very toxic, but its derivatives have been isolated from living organisms and often their toxicity is selective towards various biological targets, such as viruses, bacteria, fungi or cancer cells, which is highly desirable for drug developers. Heterocyclic compounds have at least one cyclic moiety in their molecular structure that contains at least two different types of atoms in the ring. These compounds have an essential role in drug industry, as majority of pharmaceuticals include at least one heterocyclic ring in their composition and more than 90% of these heterocyclic moieties comprise a nitrogen atom in their structure. In 2012, heterocycles could be found in each of top ten brand name small molecule drugs and 8 of them had a nitrogen atom present in the ring. Synthetic methods for the preparation of heterocyclic compounds that also include a hydrazine moiety (nitrogen-nitrogen bond) in their structure are rather scarce. Therefore, the aim of this theses was to expand possibilities for the synthesis of these novel and highly perspective compound

The Use of Computational Methods in the Toxicological Assessment of Chemicals in Food: Current Status and Future Prospects

A wide range of chemicals are intentionally added to, or unintentially found in, food products, often in very small amounts. Depending on the situation, the experimental data needed to complete a dietary risk assessment, which is the scientific basis for protecting human health, may not be available or obtainable, for reasons of cost, time and animal welfare. For example, toxicity data are often lacking for the metabolites and degradation products of pesticide active ingredients. There is therefore an interest in the development and application of efficient and effective non-animal methods for assessing chemical toxicity, including Quantitative Structure-Activity Relationship (QSAR) models and related computational methods. This report gives an overview of how computational methods are currently used in the field of food safety by national regulatory bodies, international advisory organisations and the food industry. On the basis of an international survey, a comprehensive literature review and a detailed QSAR analysis, a range of recommendations are made with the long-term aim of promoting the judicious use of suitable QSAR methods. The current status of QSAR methods is reviewed not only for toxicological endpoints relevant to dietary risk assessment, but also for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their reaction products. By referring to the concept of the Threshold of Toxicological Concern (TTC), the risk assessment context in which QSAR methods can be expected to be used is also discussed. This Joint Research Centre (JRC) Reference Report provides a summary and update of the findings obtained in a study carried out by the JRC under the terms of a contract awarded by the European Food Safety Authority (EFSA).JRC.DG.I.6-Systems toxicolog

Enantioseparations with polysaccharide-based chiral stationary phases in HPLC. Application to the enantioselective evaluation of the biodegradability of chiral drugs in activated sludge from a Valencian waste water treatment plant

The chiral nature of living systems has obvious implications for the biologically active compounds that interact with them. At the molecular level, chirality represents an intrinsic property of the essential building blocks of life, such as amino acids and sugars, and therefore, of peptides, proteins, enzymes, carbohydrates, nucleosides and a number of alkaloids and hormones. As a consequence, processes mediated by biological systems are stereochemistry-sensitive, and a pair of enantiomers can have different effects on living organisms. The scientific community has been studying the implications of chirality for life for more than a century. Today, it is still a topic of active research and debate due to the large number of chiral molecules that are part of living organisms and of our everyday life. In this context, analytical methods for the separation of the enantiomers of chiral molecules play a crucial role. Undoubtedly, the use of chiral stationary phases (CSPs) in high performance liquid chromatography (HPLC) is the preferred choice for enantioseparations. This is evidenced by the huge number of CSPs available on the market. This fact, together with the trial-and-error methods commonly used to select the most suitable chromatographic system (CSP/mobile phase combination) for a given enantioseparation, results in enormous cost and experimental effort. This makes it necessary to develop strategies to simplify this important task. This Doctoral Thesis has two clearly differentiated main objectives: (i) To contribute to the knowledge of chiral HPLC with polysaccharide-based CSPs (the most popular commercial ones: three amylose and five cellulose derivatives), and hydro-organic mobile phases (comprising acetonitrile (ACN) and methanol (MeOH) aqueous solutions compatible with aqueous matrices and mass spectrometry (MS) detection). To this end, the following specific objectives were set: (a) to contribute to a rational selection of the chromatographic system to separate the enantiomers of a given compound. To this end, the retention and enantioresolution of a large dataset of structurally unrelated chiral compounds (approximately 60 basic and neutral drugs and pesticides) in the chromatographic systems above-indicated is compared. Moreover, quantitative structure-property relationships (QSPRs) for enantioresolution related data obtained in some of the chromatographic systems studied are developed. (b) To explore the use of deconvolution of overlapping peaks to achieve the mathematical resolution when the baseline resolution cannot be achieved experimentally. To illustrate the potential of this peak model strategy, the enantioseparation of eight chiral drugs in five polysaccharide-based CSPs and ACN or MeOH hydro-organic mobile phases at different separation temperatures is considered. (ii) To contribute to the advancement of knowledge of the risks and hazards of chiral pollutants. To this end, OECD (Organisation for Economic Co-operation and Development) biodegradability tests using activated sludge from a Valencian waste water treatment plant (Quart Benàger) are performed for some common chiral pharmaceutical pollutants: trimeprazine, ibuprofen, ketoprofen, bupivacaine, mepivacaine, prilocaine and propanocaine. Next, the separation and determination of the enantiomers of the intact compound is performed using chiral HPLC methods (with amylose- or cellulose-based CSPs and ACN or MeOH hydro-organic mobile phases compatible with aqueous matrices and MS detection) developed for that purpose

Quantitative structure fate relationships for multimedia environmental analysis

Key physicochemical properties for a wide spectrum of chemical pollutants are unknown. This thesis analyses the prospect of assessing the environmental distribution of chemicals directly from supervised learning algorithms using molecular descriptors, rather than from multimedia environmental models (MEMs) using several physicochemical properties estimated from QSARs. Dimensionless compartmental mass ratios of 468 validation chemicals were compared, in logarithmic units, between: a) SimpleBox 3, a Level III MEM, propagating random property values within statistical distributions of widely recommended QSARs; and, b) Support Vector Regressions (SVRs), acting as Quantitative Structure-Fate Relationships (QSFRs), linking mass ratios to molecular weight and constituent counts (atoms, bonds, functional groups and rings) for training chemicals. Best predictions were obtained for test and validation chemicals optimally found to be within the domain of applicability of the QSFRs, evidenced by low MAE and high q2 values (in air, MAE≤0.54 and q2≥0.92; in water, MAE≤0.27 and q2≥0.92).Las propiedades fisicoquímicas de un gran espectro de contaminantes químicos son desconocidas. Esta tesis analiza la posibilidad de evaluar la distribución ambiental de compuestos utilizando algoritmos de aprendizaje supervisados alimentados con descriptores moleculares, en vez de modelos ambientales multimedia alimentados con propiedades estimadas por QSARs. Se han comparado fracciones másicas adimensionales, en unidades logarítmicas, de 468 compuestos entre: a) SimpleBox 3, un modelo de nivel III, propagando valores aleatorios de propiedades dentro de distribuciones estadísticas de QSARs recomendados; y, b) regresiones de vectores soporte (SVRs) actuando como relaciones cuantitativas de estructura y destino (QSFRs), relacionando fracciones másicas con pesos moleculares y cuentas de constituyentes (átomos, enlaces, grupos funcionales y anillos) para compuestos de entrenamiento. Las mejores predicciones resultaron para compuestos de test y validación correctamente localizados dentro del dominio de aplicabilidad de los QSFRs, evidenciado por valores bajos de MAE y valores altos de q2 (en aire, MAE≤0.54 y q2≥0.92; en agua, MAE≤0.27 y q2≥0.92)

Review of QSAR Models and Software Tools for predicting Biokinetic Properties

In the assessment of industrial chemicals, cosmetic ingredients, and active substances in pesticides and biocides, metabolites and degradates are rarely tested for their toxicologcal effects in mammals. In the interests of animal welfare and cost-effectiveness, alternatives to animal testing are needed in the evaluation of these types of chemicals. In this report we review the current status of various types of in silico estimation methods for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their metabolites/degradation products. The review was performed in a broad sense, with emphasis on QSARs and rule-based approaches and their applicability to estimation of oral bioavailability, human intestinal absorption, blood-brain barrier penetration, plasma protein binding, metabolism and. This revealed a vast and rapidly growing literature and a range of software tools. While it is difficult to give firm conclusions on the applicability of such tools, it is clear that many have been developed with pharmaceutical applications in mind, and as such may not be applicable to other types of chemicals (this would require further research investigation). On the other hand, a range of predictive methodologies have been explored and found promising, so there is merit in pursuing their applicability in the assessment of other types of chemicals and products. Many of the software tools are not transparent in terms of their predictive algorithms or underlying datasets. However, the literature identifies a set of commonly used descriptors that have been found useful in ADME prediction, so further research and model development activities could be based on such studies.JRC.DG.I.6-Systems toxicolog

Evaluation of the availability and applicability of computational approaches in the safety assessment of nanomaterials: Final report of the Nanocomput project

This is the final report of the Nanocomput project, the main aims of which were to review the current status of computational methods that are potentially useful for predicting the properties of engineered nanomaterials, and to assess their applicability in order to provide advice on the use of these approaches for the purposes of the REACH regulation. Since computational methods cover a broad range of models and tools, emphasis was placed on Quantitative Structure-Property Relationship (QSPR) and Quantitative Structure-Activity Relationship (QSAR) models, and their potential role in predicting NM properties. In addition, the status of a diverse array of compartment-based mathematical models was assessed. These models comprised toxicokinetic (TK), toxicodynamic (TD), in vitro and in vivo dosimetry, and environmental fate models. Finally, based on systematic reviews of the scientific literature, as well as the outputs of the EU-funded research projects, recommendations for further research and development were also made. The Nanocomput project was carried out by the European Commission’s Joint Research Centre (JRC) for the Directorate-General (DG) for Internal Market, Industry, Entrepreneurship and SMEs (DG GROW) under the terms of an Administrative Arrangement between JRC and DG GROW. The project lasted 39 months, from January 2014 to March 2017, and was supported by a steering group with representatives from DG GROW, DG Environment and the European Chemicals Agency (ECHA).JRC.F.3-Chemicals Safety and Alternative Method

Penitsilliinide jääkide määramine piimas läbivoolulise biosensorsüsteemi abil

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Penitsilliinid on beetalaktaamide hulka kuuluvad antibiootikumid, mida kasutatakse peamiselt Gram-positiivsete bakterite poolt tekitatud haiguste raviks. Penitsilliini ja teiste antibiootikumide jäägid piimas tekitavad inimestel allergilisi reaktsioone ning soodustavad resistentsete mikroobitüvede teket, mistõttu on antibiootikumide jääkide lubatud sisaldus toidus rangelt reguleeritud. Tavaliselt kasutatakse antibiootikumide jääkide määramiseks piimas mitmesuguseid kromatograafial põhinevaid meetodeid ning erinevaid mikroobse inhibeerimise ja immuunoretseptor teste. Kuid tihtipeale on need meetodid kallid ning aeganõudvad. Üheks võimalikuks alternatiiviks traditsioonilistele analüüsimeetoditele on biosensorite kasutamine. Biosensorite eeliseks on nende lihtsus, suhteline odavus ning kiirus, mis võimaldab nende kasutamist kiireteks analüüsideks reaalajas. Käesoleva doktoritöö eesmärgiks oli välja töötada ning testida biosensorsüsteem penitsilliinide jääkide kiireks määramiseks toorpiimas. Selleks, et kiirendada eksperimentaalsete andmete analüüsi, me pakkusime välja matemaatiline mudel biosensori kalibratsiooniparameetrite arvutamiseks ning uurisime võimalusi biosensorites toimuvate äratundmisreaktsioonide kiirendamiseks. Töö praktilises osas testisime biosensori kasutamist penitsilliinide jääkide kiireks määramiseks toorpiimas. Töö tulemusena leidsime, et glükoosi tase piimas on heaks indikaatoriks penitsilliini jääkide määramiseks toorpiimas. Seega, kasutatud biosensorsüsteem on rakendatav kiireks penitsillinide jääkide määramiseks toorpiimas piimafarmides. Kiire lüpstava piima analüüs võimaldaks mittekvaliteetse piima õigeaegset eraldamist kvaliteetsest toodangust ning kogu toodetava piima kvaliteedi tõstmist. Kasutatud biosensorsüsteemi on erinevate antibiotikumide jääkide määramiseks toorpiimas võimalik tulevikus modifitseerida täiendavate biosensorite lisamisega.The use of antibiotics for the treatment of food-producing animals generates the risk to human health due to the transmission of the residues and metabolites of these compounds into food chain. In addition, scientists and health experts also fear that wide application of antimicrobial agents, including the first discovered penicillin antibiotics, is contributing to the rise and spread of antibiotic-resistant bacteria. At present, strict regulations have been established for the levels of antibiotic residues and metabolites in food of animal origin. Antibiotic residues in food are commonly determined with the help of chromatography and special tests. The application of biosensors for the detection of antibiotic residues in milk is a good alternative to traditional methods. The benefits of biosensors are their low cost, simplicity and possibility for rapid real-time analysis. The main goal of the present work was to propose a rapid method for real-time detection of penicillins’ residues in milk, to propose a simple but sufficiently accurate model to describe the quick response of biosensor and to test this biosensorsystem. The application of the model allowed to predict optimal biosensor parameters for obtaining maximal sensitivity and high stability on one hand, and to obtain fast results from the initial phase of the reaction on the other hand. The biosensor was applied to detect the penicillins in the milk of cows with mastitis. Glucose concentration in their milk decreased significantly compared to glucose levels in high quality milk, enabling to use glucose concentration as an indicator of the presence of penicillin residues in milk. The studied biosensor set-up has high potential to serve as a system for real-time automatic control of the quality of raw milk in the milk production farms. The application of this system allows the separation of substandard milk from the milk flow prior to milk collection tank. The system can be further modified by attaching additional biosensors to build up a more robust biosensor array, where the signals of individual biosensors form a typical pattern of milk sample, which changes in the presence of different antibiotics

Production of highly efficient activated carbons from industrial wastes for the removal of pharmaceuticals from water: a full factorial design

The wide occurrence of pharmaceuticals in aquatic environments urges the development of cost-effective solutions for their removal from water. In a circular economy context, primary paper mill sludge (PS) was used to produce activated carbon (AC) aiming the adsorptive removal of these contaminants. The use of low-cost precursors for the preparation of ACs capable of competing with commercial ACs continues to be a challenge. A full factorial design of four factors (pyrolysis temperature, residence time, precursor/activating agent ratio, and type of activating agent) at two levels was applied to the production of AC using PS as precursor. The responses analysed were the yield of production, percentage of adsorption for three pharmaceuticals (sulfamethoxazole, carbamazepine, and paroxetine), specific surface area (SBET), and total organic carbon (TOC). Statistical analysis was performed to evaluate influencing factors in the responses and to determine the most favourable production conditions. Four ACs presented very good responses, namely on the adsorption of the pharmaceuticals under study (average adsorption percentage around 78%, which is above that of commercial AC), and SBET between 1389 and 1627 m2 g-1. A desirability analysis pointed out 800 °C for 60 min and a precursor/KOH ratio of 1:1 (w/w) as the optimal production conditions.publishe

Solvation thermodynamics of organic molecules by the molecular integral equation theory : approaching chemical accuracy

The integral equation theory (IET) of molecular liquids has been an active area of academic research in theoretical and computational physical chemistry for over 40 years because it provides a consistent theoretical framework to describe the structural and thermodynamic properties of liquid-phase solutions. The theory can describe pure and mixed solvent systems (including anisotropic and nonequilibrium systems) and has already been used for theoretical studies of a vast range of problems in chemical physics / physical chemistry, molecular biology, colloids, soft matter, and electrochemistry. A consider- able advantage of IET is that it can be used to study speci fi c solute − solvent interactions, unlike continuum solvent models, but yet it requires considerably less computational expense than explicit solvent simulations

Multimedia environmental fate and transport model of dichlorodiphenyltrichloethane at Sayong River watershed based on fugacity approach

Dichlorodiphenyltrichloroethane (DDT) is one of the most concerning compounds in the group of persistent organic pollutants (POPs) due to its persistence and harmfulness on environment. This thesis details the development of a multimedia environmental fate and transport model to assess the distribution and transfer processes of DDT in air, soil, water and sediment in the Sayong River watershed. Geographical Informational System (GIS) was employed to divide the watershed into up, mid and down-streams. The levels of DDT in the air, soil, water and sediment in the Sayong River watershed were monitored the period of between November 2014 and May 2015. Samples were collected and extracted through Solid Phase Extraction (SPE) and ultrasonication. Extracted samples were analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). For the development of model, the compartments and tranfer processes were setup along with the steady state and chemical equilibrium assumptions. Fugacity concept was used to formulate the distribution mechanism processes. Input parameters, consisting of chemical emission data, environmental properties and physical-chemical properties, were selected as secondary data. Microsoft Excel-Visual Basic Application (VBA) was used to encode the calculation. The total concentrations of DDT were observed to be in the range of 5.25-53.53 µg/g for soil, 0.22-37.88 µg/g for sediment and 0-0.38 µg/g for air. Meanwhile, there was no DDT found in the water samples. In addition, the model predicted reasonably accurate concentrations within an order of magnitude (0.01-0.25) in log unit. The advection outflow in air was determined to be the most important process of DDT in this model with the rate range of 0.12-0.26 mol/h. From the sensitivity analysis, the vapour pressure (Ps) and organic carbon - water partition coefficient (KOC) were concluded to be the most influential parameters where the Sensitivity Coefficient (SC) being higher than 0.5. This model is important as it can provide an efficient and cost effective measure to assess the fate and movement of DDT in the Sayong River watershed