<p>Ten years ago, the first protease inhibitor targeting the human immunodeficiency virus (HIV) was approved for clinical use. Highly active antiretroviral therapy (HAART), which combined protease and reverse transcriptase inhibitors, quickly became the standard therapy for treating patients infected with HIV and Acquired Immune Deficiency Syndrome (AIDS). Nevertheless, last year the AIDS pandemic reached its highest level ever. Many infected patients, mainly in the developing countries, are still without treatment. Among those patients who receive treatment, an increase in drug resistance and new-infection with drug-resistant strains are seen. To come to terms with these problems, new drugs that are efficient against resistant strains and can be produced at low cost are needed.</p><p>In this study, we have focused our research efforts on cyclic sulfamides active as HIV-1 protease inhibitors. Distinctive to this compound class, as compared to the inhibitors so far approved for clinical use, was the incorporation of a water mimic that displaces the structural water (W301) observed in the X-ray crystal co-complexes. The first part of the study was aimed at understanding the rationale behind the nonsymmetric binding mode that the inhibitor adopted when bound to the enzyme. Symmetric and nonsymmetric inhibitors were synthesized and the structure-activity relationships and preferable binding modes were rationalized with the help of Comparative Molecular Field Analysis (CoMFA).</p><p>In the second part of the study, an attempt was made to reduce the size of these inhibitors. As a result, the traditional P1/P1' substituents were removed, while the P2/P2' substituents were elongated in an attempt to reach between the binding sites. The design hypothesis was shown to be successful and inhibitors possessing nanomolar activity were identified.</p>

<p>This thesis is based on six papers, Papers I-VI, focusing on the interplay between the stabilizing elements of nucleic acids self-assembly; hydrogen bonding, stacking and solvent effects. In Paper I we investigate how the substitution of the O4' for CH₂ in the sugar moiety of adenosine (2'-deoxyaristeromycin) at the A⁶ position of the Dickerson-Drew dodecamer makes the two modified bases exist in a dynamic equilibrium between Hoogsteen and Watson-Crick base pairing in the NMR time scale. Paper II is a structural study of the incorporation of 1-(1',3'-<i>O</i>-anhydro-<i>β</i>-D-psicofuranosyl)thymine in the T⁷ position of the Dickerson-Drew dodecamer. NMR constrained molecular dynamics and hydration studies show the base-base distortions caused by the introduction of a North-type locked sugar in an otherwise B-type DNA•DNA duplex. Paper III shows that the stacking distortion caused by the 1-(1',3'-<i>O</i>-anhydro-<i>β</i>-D-psicofuranosyl)thymine building block perturbs the charge transfer similar to a DNA mismatch. Paper IV highlights how the sequence context affects the physico-chemical properties, monitored by the p<i>K</i><i>a</i> of guanine itself as well as how the charge perturbation is experienced by the neighboring bases, in ssDNA and ssRNA. Paper V focuses on the differences between the structural equilibria of single-stranded ssDNA and ssRNA. Directional differences in single-stranded stacking between ssDNA and ssRNA are identified and provide a basis to explain directional differences in p<i>K</i><i>a</i> modulation and dangling-end stabilization. In Paper VI the thermodynamic gains of dangling ends on DNA and RNA core duplexes are found to correlate with the X-ray geometries of dangling nucleobases relative to the hydrogen bonds of the closing base pairs.</p>

<p>Nanomaterials have attracted great interest in recent years, and are now also being considered for battery applications. Reducing the particle size of some electrode materials can increase battery performance considerably, especially with regard to capacity, power and rate capability. This thesis presents a study focused on the performance of such a material, vanadium oxide nanotubes, as cathode material for rechargeable lithium batteries.</p><p>These nanotubes were synthesized by a sol-gel process followed by hydrothermal treatment. They consist of vanadium oxide layers separated by structure-directing agents, normally amines or metal ions, e.g., Na⁺, Ca²⁺, Mn²⁺ and Cu²⁺. The layers are arranged in a scroll-like manner, allowing the interlayer structure to expand and contract, depending on the size of the embedded guest. This tubular form of vanadium oxide was able to insert lithium ions reversibly, making it a candidate cathode material. The structural and electrochemical response to lithium ion insertion was carefully studied to define optimal performance criteria and probe the lithium insertion mechanism. This was done using several characterization techniques, including X-ray diffraction, a variety of spectroscopic methods and electrochemical testing. Galvanostatic measurements show that the material can be charged and discharged reversibly for >100 cycles with a capacity of 150-200 mAh/g. The electrochemical performance is, however, dependent on the electrode film preparation technique, the choice of salt in the electrolyte and the nature of the embedded guest. Results from photoelectron spectroscopy, and soft X-ray emission and absorption spectroscopy confirm that vanadium is reduced during lithium insertion and that three oxidation states (V⁵⁺, V⁴⁺and V³⁺) co-exist at potentials below 2.0 V. <i>In situ</i> X-ray diffraction, performed during potential stepping, identifies two separate processes during lithium insertion: a fast decrease of the interlayer distance followed by a slow two-dimensional relaxation of the vanadium oxide layers. </p>

<p>This thesis contains two parts.</p><p>In the first part, general and versatile palladium-mediated ¹¹C-C bond forming reactions for use in the production of radiotracers for Positron Emission Tomography (PET) were explored. Two complimentarty approaches were investigated: the coupling of [¹¹C]methyl iodide with a vinyl stannane and the reaction of a [¹¹C]methylated stannane with various organohalides. The former approach resulted in an improved, fully automated method for the synthesis of the potential cell proliferation tracer 1-(2’-deoxy-2’-fluoro-β-D-arabinofuranosyl)-[<i>methyl</i>-¹¹C]- thymine. The tracer was obtained in an isolated decay-corrected radiochemical yield of 28% at 25 min after end of radionuclide production. </p><p>In the latter approach, a [¹¹C]methylated tricyclic stannane (5-[¹¹C]methyl-1-aza- 5-stannabicyclo[3.3.3]undecane) was synthesised in 47% decay-corrected radiochemical yield, starting from [¹¹C]methyl iodide. This stannane was successfully employed in palladium-mediated coupling reactions with aryl, heteroaryl and vinyl halides.</p><p>In the second part, effects of the osmolytes glycine betaine, trimethylamine <i>N</i>-oxide (TMAO) and urea on Ribonuclease A (RNase A) were investigated using Nuclear Magnetic Resonance (NMR) spectroscopy. Changes in the enzymatic activity in the presence of these osmolytes at concentrations of ≤1 M were observed by monitoring the RNase A-catalysed degradation of polyuridylic acid using ³¹P NMR spectroscopy. The decrease in activity caused by urea was counteracted by both glycine betaine and TMAO at a molar ratio of 1:1.4 and 1:1, respectively.</p><p>To investigate if the observed activity changes were accompanied by any detectable alteration in the gross conformation of RNase A, diffusion coefficients for the enzyme in the various osmolyte solutions were measured using pulsed-field gradient NMR. A pulse sequence suitable for diffusion measurements in highly concentrated aqueous osmolyte solutions was developed and assessed. The diffusion of RNase A was measured relative to a new internal standard, 2,2,5,5,-tetramethyl-1,4-dioxane. No clear, detectable change in the relative diffusion of RNase A was observed in these media.</p>

<p>Methods for the ¹¹C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [¹¹C]carbon monoxide at low concentration was used in transition metal- mediated reactions.</p><p>Stille couplings were employed in the synthesis of [<i>carbonyl-</i>¹¹C]ketones from methyl and aryl halides with [¹¹C]carbon monoxide. The synthesized [<i>carbonyl-</i>¹¹C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%.</p><p>A number of synthetic routes were designed using [¹¹C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [<i>carbonyl-</i>¹¹C]isocyanates, versatile precursors. [<i>carbonyl-</i>¹¹C]Isocyanate reacted via nucleophilic attack of an amine to form <i>N,N’</i>-diphenyl[¹¹C]urea in 82% analytical radiochemical yield, ethyl phenyl[¹¹C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [¹¹C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[<i>carbonyl-</i>¹¹C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [¹¹C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[¹¹C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [¹¹C]carbon monoxide in the rhodium-mediated synthesis of [<i>carbonyl-</i>¹¹C]ketenes. [<i>carbonyl-</i>¹¹C]Ketene intermediates were utilised in the synthesis of diethyl[<i>carbonyl</i>-¹¹C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[<i>carbonyl</i>-¹¹C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[<i>carbonyl</i>-¹¹C]malonate was synthesized in 50% analytical radiochemical yield. Several (<i>carbonyl-</i>¹³C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using ¹³C-NMR.</p>

<p>In vapour phase deposition, the knowledge and control of homogeneous and heterogeneous reactions in connection to precursor design may lead to the deposition of the desired material; structure or phase. This thesis is a document attempting to increase the knowledge of film growth in the B-N system.</p><p>In the present work, surface processes like adsorption, abstraction, migration and nucleation have been modelled on an atomic scale using density functional theory (DFT). The systems studied are mainly cubic and hexagonal boron nitride surfaces ((c-BN) vs. (h-BN)), but also the α-boron (001) surface.</p><p>It has been shown that DFT and a cluster approach is a reliable tool in modelling boron nitride surfaces and surface processes, provided that certain functionals, basis sets and geometrical constraints are used.</p><p>By using surface stabilisers such as H species in an electron- or radical-rich environment, it has been shown that <i>i)</i> the structure of cubic boron nitride surfaces can be sustained, and <i>ii)</i> c-BN may nucleate on the h-BN (001) basal plane. Furthermore, the nucleation of c-BN from arbitrary and experimental growth species is energetically preferable over a continuous growth of h-BN on the h-BN (001) edges.</p><p>An atomic layer deposition (ALD) process for boron nitride was developed. It resulted in turbostratic (t-BN), transparent, well-adherent and almost atomically smooth BN films. However, with the cubic phase of boron nitride absent in the ALD films, more effort needs to be put into both the theoretical and the experimental branches of this field of science.</p>

The combination of capillary electrophoresis (CE) and mass spectrometry (MS) constitutes a powerful microanalytical system in the fields of biology, medicine and chemistry. This thesis describes the development of three novel capillary coatings and demonstrates how these extend the utility of CE as a high-efficiency separation technique in protein analysis and biopharmaceutical drug screening. Due to the rapidly growing interest in characterizing the human proteome, there is an increased need for rapid protein separations. The use of CE in protein analysis is, however, nontrivial due to problems with protein adsorption to the fused-silica capillary walls. In this thesis, this problem was addressed by developing two novel, physically adsorbed, cationic polymer surface coatings, denoted PolyE-323 and Q-agarose. By using simple rinsing protocols, highly reproducible coatings, stable over a wide range of pH 2-11 were generated. Successful protein separations using cationic-coated capillaries in CE-MS, equipped with either electrospray ionization (ESI) or matrix-assisted laser desorption/ionization (MALDI), has been demonstrated. In the pharmaceutical industry, favorable pharmacokinetic properties of a candidate drug, such as high bioavailability after oral administration, are crucial for a high success rate in clinical development. Tools for prediction of biopharmaceutically relevant drug properties are important in order to identify and discard poor candidate drugs as soon as possible. In this thesis, a membrane mimetic coating was developed by electrostatically immobilizing liposomes to the capillary wall, via an anchoring sublayer of Q-agarose. The liposome-coated capillaries were demonstrated in on-line CE-MS for prediction of drug membrane permeability.

The thesis deals partly with methodology including construction of hardware and new pulse sequences in the field of electrophoretic NMR, and partly with practical use of ENMR and diffusion NMR in the investigation of charged colloidal systems. Several sources of artefacts are investigated, including gas production at the electrodes, electroosmosis and Joule heating effects that can cause convection. The electrophoretic double stimulated-echo pulse sequence is introduced to suppress these artefacts and to increase the feasible measuring range to higher electric fields and conductivities. The interaction between the non-ionic polymer poly(ethylene oxide) PEO and differently charged surfactants is investigated using the above mentioned methods. The investigated surfactants are the anionic sodium dodecyl sulphate (SDS) and potassium laurate (KC12), the cationic dodecyltrimethylammonium bromide (CTAB) and the non-ionic octyl β-D-glucoside. ENMR is also used to investigate two different mixed micelle systems, with SDS as the charged surfactant component and dodecyl malono-bis-N-methylglucamide (C12BNMG) respectively tetra(ethylene oxide) dodecyl ether (C12EO4) as the nonionic surfactant component. A method to calculate the degree of counter-ion dissociation, αdissociation, as a function of composition is demonstrated. Finally diffusion NMR is used to compare transport dynamics in gel electrolyte systems based on two differently grafted polymers; one amphiphilic system containing polymethacrylate grafted partly with polyethylene oxide and partly with fluorocarbons and the corresponding nonamphiphilic system grafted with only polyethylene oxide. Both systems contain the electrolyte lithium bis(trifluoromethylsulfonyl) imide salt dissolved in γ-butyrolactone. The results show that the system based on the amphiphilic polymer has better transport dynamics and therefore is more suited as material for battery

Future energy systems based on hydrogen as energy carrier require reliable ways for storing hydrogen gas in safe, clean and efficient ways. Metal hydrides absorb hydrogen gas reversibly, making them suitable for storage applications. Investigations of the crystal structures of these materials contribute to an understanding of the factors which can influence the absorption. Three systems, Ti3Sn-D, Nb4MSi-D (M=Co or Ni) and Pd-Ni-P, have been investigated in this thesis. Various solid state synthesis techniques have been used for sample preparation. The crystal structures have been studied using x-ray and neutron diffraction techniques. Three metal hydride phases were found in the Ti3Sn-D system upon hydrogenation. Deuterium occupies titanium octahedra and the applied deuterium pressure induces the phase transitions. The distances between the deuterium atoms increase from 2.47 Å in orthorhombic Ti3SnD0.80 to 4.17 Å in cubic Ti3SnD. The Nb4MSi-D system (M=Co or Ni) readily absorbs deuterium at room temperature and 90 kPa deuterium pressure to give a deuterium content of Nb4MSiD~2.5. Two interstitial voids, both coordinated by four niobium atoms arranged in a tetrahedral configuration, accommodate deuterium atoms. Two ternary phases and a solid solution of nickel in Pd3P have been synthesised and the crystal structures determined. PdNi2P is orthorhombic and crystallises in the MgCuAl2-type structure: an ordered derivative of the Re3B-type structure. Pd8Ni31P16 is a tetragonal high-temperature phase stable at 700°C with 110 atoms in the unit cell. Pd2.7Ni0.3P0.94 has the cementite-type structure with mixed occupancy of palladium and nickel at one of the two non-equivalent crystallographic metal positions.

Important information on the bioactive conformation of biologically active peptides may be obtained by studies of rigid peptides or well-defined secondary structure mimetics incorporated into pseudopeptides. The structural requirements for the interaction of angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) with its AT1 and AT2 receptors were the subject of this study. The main objectives of this work were to synthesize secondary structure mimetics and incorporate these into Ang II. Ang II has been suggested to adopt a turn conformation around Tyr4 when interacting with its AT1 receptor. Therefore, two γ- and one β-turn mimetic scaffolds based on the benzodiazepine structure were synthesized and decorated with side chains. The scaffolds replaced the turn region around Tyr4. Most of the pseudopeptides obtained after incorporation into Ang II exhibited high AT2/AT1 selectivity and nanomolar affinity to the AT2 receptor. One pseudopeptide encompassing a β-turn mimetic also displayed AT1 receptor affinity. We hypothesized that the position of the guanidino group of the arginine residue and the N-terminal end, in relation to the tyrosine side chain, was critical for AT2 receptor affinity. Conformational evaluation of the pseudopeptides revealed that in all the compounds with AT2 receptor affinity the arginine side chain and the N-terminal end could reach common regions, not accessible to the inactive compound. It is proposed that Ang II has a more extended bioactive conformation when binding to the AT2 receptor than when binding to the AT1 receptor. Furthermore, in a Gly scan of Ang II only replacement of the arginine residue reduced the affinity for the AT2 receptor considerably. Some N-terminal modified Ang II analogues were also synthesized and it was concluded that truncated Ang II analogues interact with the AT2 receptor differently than Ang II. Three of the synthesized pseudopeptides were evaluated in AT2 receptor functional assays and were found to act as agonists.