Academic literature on the topic 'Covalent Interactions'

Les polyphénols naturels forment des complexes non-covalents dans lesquels le π-stacking et les liaisons hydrogène jouent un rôle clé dans la stabilisation. Les calculs DFT incluant la dispersion (DFT-D), la description des processus d'agrégation non-covalente de produits naturels devient fiable. Dans ce travail, les méthodes DFT-D sont appliquées à i) la compréhension de la biosynthèse stéréo- et régio-sélective des oligostilbenoïdes, ii) la prédiction de l'agrégation des antioxydants naturels au sein de la membrane bicouche lipidique, qui pourrait rationaliser la synergie de la vitamine E, la vitamine C et polyphénols dans leur action antioxydante, et iii) la modulation des propriétés optiques de dérivés de chalcones<br>Natural polyphenols form non-covalent complexes in which π-stacking and H-bonding play a key stabilizing role. The dispersion-corrected DFT calculations have paved the way towards reliable description of aggregation processes of natural products. In this work, these methods are applied at i) understanding of stereo- and regio-selective oligostilbenoids biosynthesis; ii) predicting natural antioxidant aggregation within lipid bilayer membrane, which may allow rationalizing the synergism of vitamin E, vitamin C and polyphenols in their antioxidant action; and iii) modulating optical properties of chalcone derivatives

Lubricant formulations are highly complex mixtures, containing a multitude of additives, each geared towards improving the efficiency of often highly specialised processes. The study of lubrication, or tribology, is a huge area of research, but is often overlooked by chemists in favour of pharmaceutical or agrochemical research. This thesis lays the foundation for the study and further understanding of additive-additive interactions in a lubricant formulation. Chapter one presents a concise introduction to modern lubricant formulations by providing a historical background and examining current understanding, while focusing not on the more widely publicised engineering aspects, but on the chemical properties and mechanisms of lubricant formulations. In order to dissect out additive-additive interactions from additive-solvent interactions, a study of the biggest single component in any lubricant formulation, the base oil, is performed in Chapter two. By using a series of molecular torsion balances which have been shown to be heavily influenced by solvent effects, it is revealed that the complex multitude of available commercial base oils can be substituted with a single common lab solvent. In Chapter three, a computational reparameterisation and experimental examination of previous semi-empirical models for the prediction of hydrogen-bond energies in solution using electrostatic surface potentials was performed. Surprisingly, it was found that a simple DFT/B3LYP/6-31G* method provides a better prediction of H-bond energies in solution than more complex models or functional-group corrected methods. Chapter four focuses on the fundamental understanding of entropy and conformational flexibility of compounds in solution. Using a simple flexible experimental system, which is capable for forming an internal hydrogen bond in solution, the impact of intramolecular hydrogen bonding on the stability of an intermolecular process was studied using both experimental and computational (DFT/molecular dynamics) methods. A distinct cut-off point was observed experimentally where the intramolecular process is completely out-competed by the intermolecular interaction. A computational model which reproduces the experimental trends has yet to be found.

ESI-MS screening methods directly detect ligand-target non covalent complexes in the gas phase and allow inference of affinity (and specificity) of the ligand-target interaction in solution [1, 2]. The identity of different complexes can be directly assessed as the mass of each molecule works as intrinsic label. Biopolymers can be screened either as a single component or a mixture of different targets; in this way it is possible to determine the selectivity of a new chemical entity for different targets. On the other hand, using ESI-MS it is also possible to identify, within a mixture, components that selectively bind the active site of a certain biopolymer and could be profitably used to screen libraries of known compounds. The aim of this PhD project was the study by ESI mass spectrometry of different noncovalent complexes formed with biopolymers identified as possible therapeutic targets (Mismatch Repair Mechanism and Hsp90). The noncovalent interaction between biological targets and possible ligands were studied in order to identify potential inhibitors. The binding affinities determined by ESI-MS were compared to existing data obtained by solution phase methods. A novel MS-based method was implemented for testing different biopolymer, of therapeutic interest, against a library of fragments (molecular weight 100-300 Da) constituted of about 2,000 compounds. Particularly this approach was used for the identification of new molecules able to recognize TG mismatched base pairs in DNA that are responsible for most of the common mutations leading to formation of tumors in humans. TG mismatches are particularly abundant in cells lacking mismatch repair mechanism (MMR). MMR is involved in the correction of DNA polymerase errors that escape proofreading activity. MMR deficiency increases 50-1000-fold spontaneous mutation rates (microsatellite instability MSI) and in addition, MMR deficiency can lead to resistance to several chemotherapeutic agents (DNA damaging agent) [3]. An ESI-MS method was used to study the complexes formed between different DNA duplexes and minor groove binders and intercalator compounds. A hairpin DNA sequence (CTGGsm) bearing a single T:G mismatch and a matched hairpin DNA sequence (CCGG) were prepared and used to set up the method. Two DNA sequences were also synthesized: a self complementary G:C rich DNA sequence (HFM) and a polyAT DNA duplex (A5TG). The association constants (KAs) were directly determined from the MS spectrum and the amount of bound ligand was used to determine the selectivity of a binder among the different DNA sequences. Minor groove binders confirmed their selectivity toward AT rich DNA duplex (A5TG) whereas a tris imidazole lexitropsin derivative proved to be selective for the TG mismatched DNA hairpin (CTGGsm) in agreement with NMR, SPR, and ITC studies. A medium throughput screening (MTS) method was setup for the screening of the fragment library (about 1,000 cps) and the procedure was validated studying the interactions between the two different DNA sequences (HFM and CTGGsm) and minor groove binders. The screening was performed on the fragment library and hit compounds were afterwards tested against HFM and CCGG in order to identify selective ligands. Among the different hits identified, a slight selectivity (1.3) for the single mismatched sequence was highlighted for the fragment FBA-05-094. Twenty close analogues of FBA-05-094 were subsequently tested against CTGGsm and CCGG DNA with the aim to find more selective and higher affinity ligands. The screening of the fragment library on CTGGsm was repeated using ligand mixtures (5 and 10 components) in order to improve the assay throughput. A good agreement between the results obtained by screening the compounds as single component and in mixture was found. We investigated also the binding of small molecules towards two enzymes (PKA and Hsp90) in order to verify the possibility to apply this procedure to protein targets. Hsp90 (heat shock protein 90) is a molecular chaperone and is one of the most abundant proteins expressed in cell [4]. Targeting Hsp90 with drugs has shown promising effects in clinical trials. Inhibition of the Hsp90 ATPase machinery by natural, semi- and totally synthetic inhibitors has shown promising results in clinic. The interactions between Hsp90 and different known ligands that bind either at N or C terminal binding domains were studied and the dissociation constants for this set of ligands (KD from 0.0007 uM to 103 uM) were previously determined by fluorescence polarization (FP). We found a good agreement between these values and the percentage of bound protein determined by mass spectrometry. A screening of the fragment library against Hsp90 was performed and the resulted hit compounds were compared to those obtained by using NMR FAXS technique[5]. A good correlation was found between the data obtained by MS and NMR screenings. Competition experiments using a known ATP competitor were performed and these studies highlighted the presence of a few ATP competitor ligands in agreement with X-ray experiments. [1] Ganem B, Li Y.-T., Henion JD. Detection of noncovalent Receptor-Ligand complexes by Mass Spectrometry. Journal of American Society for Mass Spectrometry, 113, 6294-6296 (1991) [2] Hofstadler SA, Sannes-Lowery KA. Applications of ESI-MS in drug discovery: interrogation of noncovalent complexes. Nature Reviews Drug Discovery, 5(7), 585-595 (2006) [3] Stojic L., Brun R., Jiricny J., Mismatch repair and DNA damage signalling. DNA Repair, 3, 1091-1101 (2004). [4] Chaudhury S., Welch T.R., Blagg B.S., Hsp90 as a Target for Drug Development. ChemMedChem, 1331-1340 (2006). [5] Dalvit C., Fagerness P.E., Hadden D.T.A., Sarver R.W., Stockman B.J. Fluorine-NMR Experiments for High-Throughput Screening: Theoretical Aspects, Practical Considerations, and Range of Applicability. Journal of American Society for Mass Spectrometry, 125, 7696-7703 (2003)

Aquesta tesi va dirigida específicament al desenvolupament de poliuretans (PU)s funcionalitzats en la cadena lateral (FPU)s, sintetitzats a partir de diols funcionals que provenen d’àcids grassos i dos diisocianats diferents: el diisocianat d’isoforona (IPDI) i el diisocianat d’hexametilé (HDI). Aquests nous FPUs presenten una amina terciària i grups alquil, al•lil, propargil o la combinació d'aquests en la cadena lateral. Posteriorment els FPUs es modifiquen mitjançant dos mecanismes de post-polimerització basats en enllaços covalents o en enllaços no covalents.En el primer cas, es duen a terme una sèrie de reaccions fotoiniciades d’acoplament tiol-é/í entre el grup al.lil i propargil que presenten els FPUs (formats a partir de IPDI), i tioglicerol. Els hidroxi-PUs obtinguts, exhibeixen una millora del seu caràcter hidrofílic. Alternativament, els FPUs que contenen només una amina terciaria com a grup funcional situat a la cadena lateral del PU, es barregen amb diferents àcids carboxílics per donar una reacció àcid base. Els supramoleculars PUs resultants (SPU)s es caracteritzen per espectroscòpia per a verificar la presència d'enllaços iònics d'hidrogen que uneixen les cadenes de PU mitjançant interaccions fisiques. A més, es demostra la correlació existent entre l'estructura química i les propietats tèrmiques i mecàniques dels materials sintetitzats. Aquests materials presenten prometedores propietats adaptatives. Per exemple, ressalten les bones propietats de regeneració i reciclatge/remodelació, degudes al caràcter reversible de les interaccions físiques. Addicionalment, aquests elastòmers posseeixen una inherent capacitat d’autoreparació, que en termes pràctics es podria veure com una millomillora de la seva sostenibilitat. Finalment, es sintetitzen xarxes de PU que tenen un doble caràcter estructural mitjançant enllaços iònics d'hidrogen dinàmics i entrecreuaments covalents. La variació de la densitat d’entrecreuament covalent introduït per a cada una d’aquestes xarxes, produeixun ajustament sistemàtic de les propietats mecàniques i de la sensibilitat del material a la calor. Aquesta preparació demostra una via simple i eficaç per a la fabricació de poliuretans multifuncionals i l’estratègia seguida també es pot estendre a l'exploració d'altres tipus d'interaccions covalents i no covalents en polímers<br>Esta tesis está dirigida específicamente al desarrollo de poliuretanos (PU)s funcionalizados en la cadena lateral (FPU)s, sintetizados a partir de dioles funcionales que provienen de ácidos grasos y dos diisocianats diferentes; el diisocianato de isoforona (IPDI) y el diisocianato de hexametileno (HDI). Estos nuevos FPUs presentan una amina terciaria y grupos alquilo, alilo, propargilo o la combinación de éstos en posiciones de cadena lateral. Posteriormente los FPUs se modifican mediante dos mecanismos de post-polimerización basados en enlaces covalentes o en enlaces no covalentes.En el primer caso, se llevan a cabo una serie de reacciones fotoiniciadas de acoplamiento tiol-eno/ino entre el grupo alilo y propargilo que presentan los FPUs (formados a partir de IPDI), y tioglicerol. Los hidroxi-PUs obtenidos, exhiben una mejora de su carácter hidrófilo. Alternativamente, los FPUs que contienen sólo una amina terciaria como grupo funcional situado en la cadena lateral del PU, se mezclan con diferentes ácidos carboxílicos mediante una reacción de ácido base. Los PUs supramoleculares resultantes (SPU)s se caracterizan por espectroscopia para verificar la presencia de enlaces iónicos de hidrógeno que unen las cadenas de PU formando interacciones físicas. Además, se demuestra la correlación existente entre la estructura química y las propiedades térmicas y mecánicas de los materiales sintetizados. Estos materiales presentan prometedoras propiedades adaptativas. Por ejemplo, resaltan las buenas propiedades de regeneración y reciclaje/remodelación, debidas al carácter reversible de las interacciones físicas. Adicionalmente, estos elastómeros poseen una inherente capacidad de autorautorreparación, que en términos prácticos se podría ver como una mejora de su sostenibilidad. Finalmente, se sintetizan redes de PU que tienen un doble carácter estructural mediante enlaces iónicos de hidrógeno dinámicos y entrecruzamientos covalentes. La variación de la densidad de entrecruzamiento covalente introducido para cada una de estas redes produce un ajuste sistemático de las propiedades mecánicas y la sensibilidad del material al calor. Esta preparación demuestra una vía simple y eficaz para la fabricación de poliuretanos multifuncionales.<br>This Thesis is addressed to the development of side-chain functionalized polyurethanes (FPU)s, with enhanced properties, made from fatty acid-based functional diols and two different diisocyanates; isophorone diisocyanate (IPDI) and hexamethylene diisocyanate (HDI). The novel FPUs present tertiary amine and alkyl, allyl, propargyl moieties or the combination of these, as side-chain positions groups. The FPUs were further modified via two post-polymerization mechanisms based on covalent or non-covalent bonds. In the first case, photoinitiated thiol-ene/yne coupling reaction between allyl, propargyl-functionalized PUs (based on IPDI) and thioglycerol was carried out. Obtained hydroxyl-PUs exhibit different thermal and mechanical properties in comparison with precursor PUs. Moreover, the incorporation of hydroxyl groups leads to PUs with enhanced hydrophilicity. Alternatively, the FPU (based on IPDI) containing only tertiary amine pendant group was mixed with different carboxylic acids in an acid-base reaction. Supramolecular ionic PUs were characterized by spectroscopic tools to verify the presence of ionic hydrogen bond as ionic interaction. Correlation between structure and thermal and mechanical properties was demonstrated. Samples show rapid thermal reversibility and recyclability thanks to the reversible bonds. In addition, elastomeric supramolecular PUs networks were prepared from HDI and aminodiol. The resulting materials exhibit some promising adaptive material properties such as effective energy dissipation upon deformation through unzipping the ionic hydrogen bonding network, combined with good shape-regeneration property and recycling/reshaping capability arising from their recoverable nature. More importantly, the resulting biobased elastomers possess the inherent self-healing ability, which can be seen as an upgrade of their sustainability.A novel thermo-reversible network is constructed by the thiol-ene functionalized polyurethane via dynamic ionic hydrogen bonds and covalent cross-links. By varying the covalent cross-linking density, the mechanical properties and the stimuli-responsive behaviour can be systematically tuned. This synthesis demonstrates a simple and effective pathway to fabricate multifunctional polyurethanes with desired functions.

Non-covalent interactions underpin the whole of chemistry and biology, but their study is extremely difficult in complicated biological systems. This thesis presents the application of synthetic molecular balances for gaining fundamental insights into the physicochemical phenomena that govern molecular recognition processes. Chapter 1 reviews the use of small synthetic molecules that exist in two conformational states via slow rotation of a bond, in the quantification of non-covalent interactions. Chapter 2 presents a new molecular torsion balance, based on a slowly rotating tertiary formyl amide for the study of non-covalent interactions. The incorporation of a fluorine atom in one of the rings allows the quantification of solvent effects in a wide range of solvents. Intramolecular electrostatic interactions and intermolecular solvation effects (but not solvophobic effects) are shown to be important in determining the position of the conformational equilibria. Correlations with calculated molecular properties show that solvent effects are fully dissected, revealing the idealistic behavior of the system in the gas phase. Chapter 3 discusses through-space substituent effects on the properties of aromatic rings. Electronic communication between both electron-rich and electron-deficient substituents with the electron density of an adjacent aromatic ring is predicted by molecular electrostatic potential calculations. The effect is confirmed to occur experimentally and is quantified using synthetic molecular balances. Chapter 4 describes the work done towards the investigation of solvent bridging interactions in molecular torsion balances. No experimental evidence of bridging interactions was observed. This might be attributed to the entropic penalty associated with this binding mode, or the non-ideal geometry of the potential bridging sites. Chapter 5 outlines a steric blocking effect observed in certain balances with bulky substituents in chloroform and dichloromethane. Chapter 6 presents synthetic procedures and compound characterisation including a thorough analysis of NMR data obtained in this study.

In this thesis, the design and synthesis of novel C60 fullerene compounds with different functional groups is reported. Chapter 1 introduces the background of the project with a general introduction into the covalent and non-covalent types of bonding interactions, and the chemistry and reactions of C60 fullerenes. Chapter 2 focuses on co-crystallisation of pristine C60 with selected aromatic compounds. Single crystals have been obtained and characterised by X-ray diffraction. Chapter 3 is concerned with the synthesis and characterisation of novel fullerene compounds by using Prato cycloaddition reactions, such novel compounds are further characterised in the solid state by single crystal X-ray diffraction. Hirshfeld surfaces are used to investigate the non-covalent interaction of the obtained crystal structures. Chapter 4 describes the synthesis and characterisation of novel fullerene compounds by using Bingel cycloaddition reactions. Crystallisation experiments have been attempted and theoretical studies using the semi-empirical method, parameterized model number 3, have been employed to investigate the charge transfer between the ligand and the C60 molecule. The novel molecules in this work have been characterised by infrared and NMR spectroscopies, and mass spectrometry. Single crystal X-ray diffraction was used when appropriate.

Non-covalent interactions in solution are subject to modulation by surrounding solvent molecules. This thesis presents two experimental molecular balances that have been used to quantify solvent effects on non-covalent interactions, including electrostatic and dispersion interactions. The first chapter introduces literature where non-covalent interactions have been studied in a range of solvents, particularly those where the effects of aqueous or fluorous solvents have been investigated. These solvents are of particular interest as they both invoke solvophobic effects on organic molecules, but have differing chemical and physical properties. The second chapter describes the adaptation of the Wilcox molecular torsion balance to study interactions between organic and fluorinated carbon chains in a range of solvents. Solvent cohesion was found to be the principle force driving both the alkyl and fluorous chains together in aqueous solvents, where no contribution to the interaction energy arising from dispersion forces could be detected. In fluorous and polar organic solvents evidence was found for weak favourable dispersion interactions between the alkyl chains. In contrast dispersion forces between the chains were found to be disrupted by competitive van der Waals interactions with surrounding solvent molecules in apolar organic solvents. Association of the fluorous chains was found to be solely driven by solvent cohesion. The final chapter describes the design and synthesis of a novel synthetic molecular-balance framework and describes its application to simultaneously measure solvent and substituent effects on the position of conformational equilibria. Despite the simplicity of the model system, surprisingly complicated behaviour emerged from the interplay of conformational, intramolecular and solvent effects. Nonetheless, a large data set of experimental equilibrium constants was analysed using a simple solvent model, which was able to account for both the intuitive and more unusual patterns observed. A means of dissecting electrostatic and solvent effects to reveal pseudo gas-phase behaviour has resulted from the analysis of experimental data obtained in many solvents.