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Modeling and simulations of some anisotropic soft-matter systems: from biaxial to chiral materialsQuerciagrossa, Lara <1985> 17 April 2013 (has links)
We have modeled various soft-matter systems with molecular dynamics (MD) simulations.
The first topic concerns liquid crystal (LC) biaxial nematic (Nb) phases, that can be possibly used in fast displays. We have investigated the phase organization of biaxial Gay-Berne (GB) mesogens, considering the effects of the orientation, strength and position of a molecular dipole. We have observed that for systems with a central dipole, nematic biaxial phases disappear when increasing dipole strength, while for systems characterized by an offset dipole, the Nb phase is stabilized at very low temperatures.
In a second project, in view of their increasing importance as nanomaterials in LC phases, we are developing a DNA coarse-grained (CG) model, in which sugar and phosphate groups are represented with Lennard-Jones spheres, while bases with GB ellipsoids. We have obtained shape, position and orientation parameters for each bead, to best reproduce the atomistic structure of a B-DNA helix. Starting from
atomistic simulations results, we have completed a first parametrization of the force field terms, accounting for bonded (bonds, angles and dihedrals) and non-bonded interactions (H-bond and stacking). We are currently validating the model, by investigating stability and melting temperature of various sequences.
Finally, in a third project, we aim to explain the mechanism of enantiomeric discrimination due to the presence of a chiral helix of poly(gamma-benzyl L-glutamate) (PBLG), in solution of dimethylformamide (DMF), interacting with chiral or pro-chiral molecules (in our case heptyl butyrate, HEP), after tuning properly an atomistic force field (AMBER). We have observed that DMF and HEP molecules solvate uniformly the PBLG helix, but the pro-chiral solute is on average found closer to the helix with respect to the DMF. The solvent presents a faster isotropic diffusion, twice as HEP, also indicating a stronger interaction of the solute with the helix.
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Sintesi di molecole biologicamente attive con tecniche chemoenzimatiche:beta-lattami, profeni e alfa-amminoacidi non naturali / Synthesis of biologically active molecules by using chemoenzymatic techniques:beta-lactams, profens and unnatural alfa-amino acidsPori, Matteo <1983> 22 April 2013 (has links)
Il progetto di ricerca di questa tesi è stato focalizzato sulla sintesi di tre classi di molecole: β-lattami, Profeni e α-amminonitrili, utilizzando moderne tecniche di sintesi organica, metodologie ecosostenibili e strategie biocatalitiche.
I profeni sono una categoria di antiinfiammatori molto diffusa e in particolare abbiamo sviluppato e ottimizzato una procedura in due step per ottenere (S)-Profeni da 2-arilpropanali raceme. Il primo step consiste in una bioriduzione delle aldeidi per dare i relativi (S)-2-Aril Propanoli tramite un processo DKR mediato dall’enzima Horse Liver Alcohol Dehydrogenase. Il secondo, l’ossidazione a (S)-Profeni, è promossa da NaClO2 e TEMPO come catalizzatore. Con lo scopo di migliorare il processo, in collaborazione con il gruppo di ricerca di Francesca Paradisi all’University College Dublino abbiamo immobilizzato l’enzima HLADH, ottenendo buone rese e una migliore enantioselettività. Abbiamo inoltre proposto un interessante approccio enzimatico per l’ossidazione degli (S)-2-Aril Propanoli utilizzando una laccasi da Trametes Versicolor.
L’anello β-lattamico è un eterociclo molto importante, noto per essere un interessante farmacoforo. Abbiamo sintetizzato nuovi N-metiltio beta-lattami, che hanno mostrato un’attività antibatterica molto interessante contro ceppi resistenti di Staphilococcus Aureus prelevati da pazienti affetti da fibrosis cistica. Abbiamo poi coniugato gruppi polifenolici a questi nuovi β-lattami ottenendo molecule antiossidanti e antibatteriche, cioè con attività duale. Abbiamo poi sintetizzato un nuovo ibrido retinoide-betalattame che ha indotto differenziazione si cellule di neuroblastoma. Abbiamo poi sfruttato la reazione di aperture dell’anello monobattamico tramite enzimi idrolitici, con lo scopo di ottenere β-amminoacidi chirali desimmetrizzati come il monoestere dell’acido β–amminoglutammico.
Per quando riguarda gli α-amminonitrili, è stato sviluppato un protocollo di Strecker. Le reazioni sono state molto efficienti utilizzando come fonte di cianuro l’acetone cianidrina in acqua, utilizzando differenti aldeidi e chetoni, ammine primarie e secondarie. Per mettere a punto una versione asimmetrica del protocollo, abbiamo usato ammine chirali con lo scopo di ottenere nuovi α-amminonitrili chirali. / The research project of this thesis has been focused on the synthesis of three class of molecules: β-lactams, Profens and α-aminonitriles by using modern techniques of organic synthesis, favouring sustainable and green methodologies, especially biocatalytic strategies.
Profens are a very important and widespread category of pain killer and in particular we developed and optimized a two steps procedure to obtain (S)-Profens from racemic 2-aryl propanals. The first step was a bioreduction of the aldehydes to (S)-2-Aryl Propanols with a DKR process mediated by Horse Liver Alcohol Dehydrogenase (HLADH); the second one was a “green oxidation” to (S)-Profens promoted by NaClO2 and TEMPO/NaClO as catalyst. To improve the whole two-step process, in a collaboration with the research group of Francesca Paradisi at the University College of Dublin we immobilized a modified HLADH, with good yields and better enantioselectivity. We also proposed an interesting enzymatic approach for the oxidation of (S)-2-Aryl Propanols by using Laccase from Trametes Versicolor.
β-lactam ring is a very important heterocycle, known to be an interesting pharmacophore. We synthesized new N-methylthio monobactams which showed an interesting antibacterial activity against resistant strains of Staphilococcus Aureus collected from patients of cystic fibrosis. We then conjugated polyphenolic groups to the new monobactams obtaining molecules with antioxidant and antibacterial with dual-activity. A new hybrid retinoid-β-lactam was developed which induced differentiation on neuroblastoma cells. The ring opening of monobactams by hydrolytic enzymes was investigated to access desymmetrizated chiral β-aminoacids such as beta-aminoglutamic acid monoesters.
For what concerns the third class of molecules reported, the α-aminonitriles, a new Strecker protocol was developed. Reactions worked very well in water by using acetone cyanohydrin as cyanide source with different aldehydes and ketones and primary or secondary amines; to provide an asymmetric version of our protocol we used chiral amines from chiral pool obtaining new chiral α-aminonitriles.
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De Novo Design of Foldamers for Preparation of Nanostructured Materials / De Novo Design di foldameri per la preparazione di materiali nanostrutturatiCastellucci, Nicola <1984> 22 April 2013 (has links)
This thesis deals with the synthesis and the conformation analysis of hybrid foldamers containing the 4-carboxyoxazolidin-2-one unit or related molecules, in which an imido-type function is obtained by coupling the nitrogen of the heterocycle with the carboxylic acid moiety of the next unit.
The imide group is characterized by a nitrogen atom connected to an endocyclic and an exocyclic carbonyl, which tend always to adopt the trans conformation. As a consequence of this locally constrained disposition effect, these imide-type oligomers are forced to fold in ordered conformations.
The synthetic approach is highly tuneable with endless variations, so, simply by changing the design and the synthesis, a wide variety of foldamers with the required properties may be prepared “on demand”.
Thus a wide variety of unusual secondary structures and interesting supramolecular materials may be obtained with hybrid foldamers.
The behaviour in the solid state of some of these compounds has been analyzed in detail, thus showing the formation of different kinds of supramolecular materials that may be used for several applications.
A winning example is the production of a bolaamphiphilic gelators that may also be doped with small amounts of dansyl containing compounds, needed to show the cellular uptake into IGROV-1 cells, by confocal laser scanning microscopy. These gels are readily internalized by cells and are biologically inactive, making them very good candidates in the promising field of drug delivery.
In the last part of the thesis, a particular attention was directed to the search of new scaffolds that behave as constrained amino acid mimetics, showing that tetramic acids derivatives could be good candidates for the synthesis and applications of molecules having an ordered secondary structure. / Il lavoro di ricerca svolto nel triennio di frequenza della Scuola di Dottorato in Scienze Chimiche ha avuto come obiettivo la sintesi e l’analisi conformazionale di molecole sintetiche, appartenenti alla classe dei foldameri pseudopeptidici. La maggior parte delle molecole sintetizzate hanno come nucleo centrale un’unità eterociclica derivante dalla treonina detta ossazolidinone. Gli acil-derivati di questo scaffold sintetico hanno la particolarità di assumere strutture secondarie stabili e ben definite. In questo ambito è stata messa a punto la sintesi di etero‐oligomeri (contenenti due o più diversi amminoacidi naturali o sintetici), sia lineari sia ciclici per mimare strutture secondarie come eliche, turns o sheets.
Alcune classi di oligomeri tendono ad assumere una struttura ordinata in fase solida, presentandosi sotto forma di fibrille osservabili al microscopio ottico. Alcuni composti hanno mostrato interessanti proprietà come gelator, cioè composi in grado di formare gel sia con acqua che con solventi organici. Tali gel si sono dimostrati anche buoni complessanti per sali metallici.
Sia i monomeri che gli oligomeri sono stati sintetizzati utilizzando metodi di coupling in soluzione. Una particolare attenzione è stata riposta nella purificazione delle varie molecole.
Oltre ai composti di natura ossazolidinonica, è stata valutata la sintesi di altri scaffold sintetici che, una volta inseriti in strutture molecolari più complesse, danno origine a molecole in grado di essere classificate come foldameri. Una parte consistente dell’attività di laboratorio è stata volta alla sintesi di acidi tetrammici, eterocicli ricorrenti in natura. Un’analisi conformazionale delle molecole sintetizzate ha dimostrato come anche questo tipo di molecole sia in grado di auto assemblarsi in strutture secondarie ordinate.
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Celle ad Ossidi Solidi per Elettrolisi ad Alta Temperatura / Solid Oxide Cells for High Temperature ElectrolysisGondolini, Angela <1985> 12 April 2013 (has links)
Lo scopo di questa tesi è stato la produzione di un elettrolizzatore ad ossidi solidi (SOEC) mediante tecniche economiche e facilmente industrializzabili. Fondamentale a questo scopo è stata la realizzazione di una semicella costituita da un anodo poroso a base di La0.8Sr0.2MnO3-Ce0.8Gd0.2O2-δ (LSM-GDC) ed un elettrolita denso a base di Ce0.8Gd0.2O2-δ (GDC). Le tecniche utilizzate per la produzione di questo sistema sono state il colaggio su nastro e la serigrafia. Anche se generalmente, le celle SOEC vengono prodotte catodo supportate, in questo studio, l’elemento supportante scelto è stato l’anodo poiché questo garantisce una migliore stabilità meccanica all’intera cella. Tale substrato è stato ottenuto mediante colaggio su nastro accoppiato con un metodo innovativo di sinterizzazione denominato sinterizzazione reattiva, processo che prevede la formazione della fase di interesse durante un unico trattamento termico di eliminazione degli additivi organici e consolidamento del manufatto finale. La membrana elettrolitica per l’ottenimento del bilayer anodo-elettrolita, è stata prodotta mediante sia serigrafia che colaggio su nastro. L’accurato studio dell’evoluzione di fase della polvere anodica, l’ottimizzazione della sospensione per colaggio su nastro e dei trattamenti termici hanno permesso l’ottenimento di anodi (fino a dimensioni di 10x10 cm2). Lo studio dei profili di sinterizzazione delle polveri anodica ed elettrolitica e dell’influenza della tecnica di formatura sulla sinterabilità dei layer elettrolitici prodotti hanno inoltre permesso l’ottenimento di una semicella planare costituita da un elettrodo poroso ed una membrana elettrolitica densa adatte per applicazioni SOEC. / The aim of this thesis was the production of a solid oxide electrolyzer cell (SOEC) through cheap and easily scalable techniques. For doing so the most important step is the production of the bilayer supporting electrode/electrolyte. Therefore a half-cell constituted by a porous La0.8Sr0.2MnO3-Ce0.8Gd0.2O2-δ (LSM-GDC) anode and a dense Ce0.8Gd0.2O2-δ (GDC) electrolyte was produced. Tape casting and screen printing were the techniques used for the production of this bilayer. Even if, the typical supporting element for an electrolyzer cells is the cathode, in this study an anode-supported cell was produced in order to assure a better mechanical stability. The supporting anode was produced by tape casting using an innovative sintering method called reactive sintering. With this method the final phase was obtained during a single thermal treatment that included also the organic removal and the final consolidation of the substrate. The electrolytic membrane was produced using either screen printing and tape casting. Anode substrates (of dimensions up to 10x10 cm2) were produced though a careful study of the phase evolution of the anodic reagents powder, the optimization of the tape casting slurry and the thermal treatments of debonding and sintering. The careful study of the sintering profiles of the anodic and electrolytic powders and of the effect of the shaping method on the sintering properties of the electrolyte layers allowed the production of flat half-cell constituted of porous electrode and dense electrolyte, suitable for SOEC application.
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Innovative Strategies for the Synthesis of Biologically Active Small MoleculesGiacomini, Elisa <1983> 30 April 2013 (has links)
The post genomic era, set the challenge to develop drugs that target an ever-growing list of proteins associated with diseases. However, an increase in the number of drugs approved every year is nowadays still not observed. To overcome this gap, innovative approaches should be applied in drug discovery for target validation, and at the same time organic synthetic chemistry has to find new fruitful strategies to obtain biologically active small molecules not only as therapeutic agents, but also as diagnostic tools to identify possible cellular targets.
In this context, in view of the multifactorial mechanistic nature of cancer, new chimeric molecules, which can be either antitumor lead candidates, or valuable chemical tools to study molecular pathways in cancer cells, were developed using a multitarget-directed drug design strategy. According to this approach, the desired hybrid compounds were obtained by combining in a single chemical entity SAHA analogues, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives able to block cell cycle, to induce apoptosis and cell differentiation and with Sorafenib derivative, a multikinase inhibitor. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on leukemia Bcr-Abl-expressing K562 cell lines, as well as their HDACs inhibition. Preliminary results confirmed that one of the hybrid compounds has the desired chimeric profile.
A distinct project was developed in the laboratory of Dr Spring, regarding the synthesis of a diversity-oriented synthesis (DOS) library of macrocyclic peptidomimetics. From a biological point of view, this class of molecules is extremely interesting but underrepresented in drug discovery due to the poor synthetic accessibility. Therefore it represents a valid challenge for DOS to take on. A build/couple/pair (B/C/P) approach provided, in an efficient manner and in few steps, the structural diversity and complexity required for such compounds.
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Determinazione di radicali OH: sintesi di materiali per la modifica di elettrodi di platino e carbone vetroso / OH radical Determination: synthesis of materials used for the modification of Pt and Glassy Carbon electrodesGualandi, Isacco <1985> 17 April 2013 (has links)
Questa tesi descrive lo sviluppo di un elettrodo modificato con un polimero isolante per la determinazione indiretta del radicale OH. I polimeri testati sono stati polifenolo, polipirrolo e polipirrolo sovraoossidato ed il primo è risultato quello con le migliori prestazioni. Il film di modificante è stato depositato per elettropolimerizzazione del fenolo in ambiente acido, su un elettrodo di carbone vetroso (GC) ed è risultato isolante e perfettamente adeso al GC, impedendo il trasferimento di carica alle più comuni sonde redox. L’attacco dei radicali OH, generati dalla reazione di Fenton o dalla fotolisi di H2O2, rimuove parzialmente il polimero dal GC, ripristinando parzialmente il comportamento conduttore dell’elettrodo. L’entità della degradazione del film polifenolico è stata valutata sfruttando la corrente relativa alla sonda redox Ru(NH3)63+, che rappresenta il segnale analitico per la determinazione del radicale OH. L’elettrodo è stato impiegato per stimare le prestazioni di foto catalizzatori a base di nanoparticelle di TiO2, ottenendo risultati correlati a quelli ricavati da un metodo HPLC. Inoltre esso è stato usato per sviluppare una nuova procedura per la determinazione della capacità di scavenging verso i radicali OH, che è stata applicata all’analisi di composti puri e campioni reali. I risultati erano confrontabili con quelli determinati con metodiche standardizzate, comunemente impiegate per la determinazione della capacità antiossidante. Inoltre è stato condotto uno studio riguardante la modifica di un elettrodo di platino con un idrossido misto a strati a base di cobalto e alluminio (LDH). In particolare si sono valutati gli effetti di diversi pretrattamenti del Pt sulle caratteristiche e prestazioni elettrocatalitiche del film di LDH nei confronti dell’ossidazione di anilina, fenolo e acido salicilico. Questi composti possono essere impiegati come molecole sonda per la determinazione del radicale OH e rivestono interesse da un punto di vista elettroanalitico perché portano facilmente alla passivazione della superficie di Pt. / The development of a cheap modified electrode for the indirect detection of OH radical is described. The method is based on the attack of OH radicals on the modifier and the quantification of its degradation is evaluated by electroanalytical approaches. Polyphenol, polypyrrole and overoxidized polypyrrole were tested as modifiers for the determination and, from our experiments, polyphenol resulted the best one. The modified electrode was prepared by electropolymerization of phenol in acid environment on glassy carbon (GC). The film perfectly covered the GC surface and inhibited the charge transfer of many redox species. The attack of OH radicals generated by Fenton reaction or H2O2 photolysis partly removed the polymer from GC and the conductor behavior of the electrode was partially restored. The degree of degradation of the polyphenol is the analytical signal and was quantified by cyclic voltammetry and chronoamperometry, using the redox probe Ru(NH3)63+. The electrode was used to evaluate the performances of different photocatalysts based on TiO2 nanoparticles and the results were successfully compared with those obtained from a more traditional HPLC method. A new procedure for the determination of the scavenging activity towards OH radicals was developed using the polyphenol modified GC. The results obtained for pure compounds and real samples were comparable to those from standardized methods which are widely employed to estimate the antioxidant capacity. Furthermore, the modification of a Pt electrode with a double layered hydroxide, based on Co and Al, (LDH) was deeply investigated. In particular, we studied the effects of different pretreatments of Pt surface on the characteristics and performances of the LDH film towards the electrocatalytic oxidation of aniline, phenol and salicylic acid. These compounds can be used as probe molecules for hydroxyl radical detection and are very interesting from an electroanalytical point of view since they lead to Pt passivation.
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Electrochemical sensing strategies for the detection of interactions between biological macromoleculesOnofri, Manuele <1983> 22 April 2013 (has links)
Electrochemical biosensors provide an attractive means to analyze the content of a biological sample due to the direct conversion of a biological event to an electronic signal, enabling the development of cheap, small, portable and simple devices, that allow multiplex and real-time detection. At the same time nanobiotechnology is drastically revolutionizing the biosensors development and different transduction strategies exploit concepts developed in these field to simplify the analysis operations for operators and end users, offering higher specificity, higher sensitivity, higher operational stability, integrated sample treatments and shorter analysis time.
The aim of this PhD work has been the application of nanobiotechnological strategies to electrochemical biosensors for the detection of biological macromolecules.
Specifically, one project was focused on the application of a DNA nanotechnology called hybridization chain reaction (HCR), to amplify the hybridization signal in an electrochemical DNA biosensor. Another project on which the research activity was focused concerns the development of an electrochemical biosensor based on a biological model membrane anchored to a solid surface (tBLM), for the recognition of interactions between the lipid membrane and different types of target molecules.
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Investigation of heterogeneous catalysts for the synthesis of fine chemicalsGiugni, Alessandra 12 April 2013 (has links)
In order to match the more stringent environmental regulations, heterogenization of traditional homogeneous processes is one of the main challenges of the modern chemical industry. Great results have been achieved in the fields of petrochemicals and base chemicals, whereas in fine chemical industry most of the synthetic procedures are based on multistep processes catalyzed by homogeneous catalysts mainly used in stoichiometric amounts. In the fine chemicals manufacture not so much efforts have been devoted to the investigation of suitable solid catalysts for the development of greener processes, then this sector represent a very attractive field of research. In this context, the present work deals with the extensive investigation of the possibility to heterogenize existing processes, in particular two different classes of reactions have been studied: alkylation of aromatic and heteroaromatic compounds and selective oxidation of aromatic alcohols. Traditional solid acid catalysts, such as zeolites, clays and alumina have been tested in the gas phase alkylation of 1,2-methylendioxybenzene, core building block of many drugs, pesticides and fragrances. The observed reactivity were clarified through a deep FTIR investigation complemented by ab initio calculation. The same catalysts were tested in the gas phase isopropylation of thiophene with the aim of clearly attribute the role of the reaction parameters in the reaction proceeding and verify the possibility to enhance the selectivity of one of the two possible isomers. Finally various Au/CeO2 catalysts were tested in the synthesis of benzaldehyde and piperonal, two aldehydes largely employed in the manufacture of fine chemical products, through liquid phase oxidation of the corresponding alcohols in very mild conditions.
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Studies of pure rotational spectra of isolated molecules and molecular adducts using pulsed jet Fourier transform microwave (PJ-FTM) spectroscopyFeng, Gang <1984> 22 April 2013 (has links)
This thesis focuses on studying molecular structure and internal dynamics by using pulsed jet Fourier transform microwave (PJ-FTMW) spectroscopy combined with theoretical calculations. Several kinds of interesting chemical problems are investigated by analyzing the MW spectra of the corresponding molecular systems.
First, the general aspects of rotational spectroscopy are summarized, and then the basic theory on molecular rotation and experimental method are described briefly. ab initio and density function theory (DFT) calculations that used in this thesis to assist the assignment of rotational spectrum are also included.
From chapter 3 to chapter 8, several molecular systems concerning different kind of general chemical problems are presented. In chapter 3, the conformation and internal motions of dimethyl sulfate are reported. The internal rotations of the two methyl groups split each rotational transition into several components line, allowing for the determination of accurate values of the V3 barrier height to internal rotation and of the orientation of the methyl groups with respect to the principal axis system.
In chapter 4 and 5, the results concerning two kinds of carboxylic acid bi-molecules, formed via two strong hydrogen bonds, are presented. This kind of adduct is interesting also because a double proton transfer can easily take place, connecting either two equivalent or two non-equivalent molecular conformations.
Chapter 6 concerns a medium strong hydrogen bonded molecular complex of alcohol with ether. The dimer of ethanol-dimethylether was chosen as the model system for this purpose.
Chapter 7 focuses on weak halogen…H hydrogen bond interaction. The nature of O-H…F and C-H…Cl interaction has been discussed through analyzing the rotational spectra of CH3CHClF/H2O. In chapter 8, two molecular complexes concerning the halogen bond interaction are presented.
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New synthetic bile acid analogue agonists of FXR and TGR5 receptors: Analytical methodologies for the study of their physico-chemical properties, pharmacokinetic activity and metabolism.Colliva, Carolina <1981> 30 April 2013 (has links)
This thesis reports an integrated analytical approach for the study of physicochemical and biological properties of new synthetic bile acid (BA) analogues agonists of FXR and TGR5 receptors. Structure-activity data were compared with those previous obtained using the same experimental protocols on synthetic and natural occurring BA.
The new synthetic BA analogues are classified in different groups according also to their potency as a FXR and TGR5 agonists: unconjugated and steroid modified BA and side chain modified BA including taurine or glycine conjugates and pseudo-conjugates (sulphonate and sulphate analogues).
In order to investigate the relationship between structure and activity the synthetic analogues where admitted to a physicochemical characterization and to a preliminary screening for their pharmacokinetic and metabolism using a bile fistula rat model. Sensitive and accurate analytical methods have been developed for the quali-quantitative analysis of BA in biological fluids and sample used for physicochemical studies.
Combined High Performance Liquid Chromatography Electrospray tandem mass spectrometry with efficient chromatographic separation of all studied BA and their metabolites have been optimized and validated. Analytical strategies for the identification of the BA and their minor metabolites have been developed. Taurine and glycine conjugates were identified in MS/MS by monitoring the specific ion transitions in multiple reaction monitoring (MRM) mode while all other metabolites (sulphate, glucuronic acid, dehydroxylated, decarboxylated or oxo) were monitored in a selected-ion reaction (SIR) mode with a negative ESI interface by the following ions.
Accurate and precise data where achieved regarding the main physicochemical properties including solubility, detergency, lipophilicity and albumin binding . These studies have shown that minor structural modification greatly affect the pharmacokinetics and metabolism of the new analogues in respect to the natural BA and on turn their site of action, particularly where their receptor are located in the enterohepatic circulation.
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