This thesis describes the synthesis of molecules designed for inhibition of two aspartic proteases, viral HIV-1 PR and human BACE-1. It also reports on the structure activity relationships of the targeted enzyme inhibitors. It is estimated that currently 33 million people are infected with HIV, the causative agent of AIDS. The virus targets T-lymphocytes and macrophages of the human immune system. The HIV-1 PR plays an important role in the viral replication, and by inhibiting the enzyme the disease progression can be slowed down or even halted. Herein is reported the design and synthesis of a series of HIV-1 PR inhibitors with novel P2 substituents of which several inhibit the enzyme in the nanomolar range. The aim of the second work was to further develop the inhibitors by the introduction of fluorine. Several attempts were performed to fluorinate different P2-substituents. Alzheimer’s disease (AD) is neurodegenerative, progressive and fatal disorder of the brain. It is associated with accumulation of plaques and tangles that cause impairment and functional decline of brain tissue which result in loss of memory and cognition. The plaques are mainly constituted of amyloid-β peptides that are generated in two steps from the amyloid precursor protein (APP). The cleavage sequence is initiated by the aspartic protease BACE-1, which makes the enzyme a key target in the effort of finding a therapy that aim to slow down the progression of AD. Herein are enclosed the development of two series of potent BACE-1 inhibitors. In the first work a synthetic strategy was developed to truncate a previously reported hydroxyethylene core structure in order to generate more drug-like inhibitors. This generated a series of truncated inhibitors where two amide bonds have been replaced with an ether - or alternatively a secondary amine linkage. A number of these inhibitors show potency against BACE-1. In the second part of the work the aim was investigate the effect of alterations in the P1 position. Five scaffolds with new P1 substituents were designed, synthesized and coupled with two different P2-P3 substituents. This resulted in a series of potent inhibitors that inhibit BACE-1 in the nanomolar range. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 2: Submitted. Paper 3: Manuscript.

The first part of this thesis addresses the design and synthesis of amine building blocks accomplished by applying two different synthetic procedures, both of which were developed using solid-phase chemistry. Chapter 1 presents the first of these methods, entailing a practical solid-phase parallel synthesis route to N-monoalkylated aminopiperidines and aminopyrrolidines achieved by selective reductive alkylation of primary and/or secondary amines. Solid-phase NMR spectroscopy was used to monitor the reactions for which a new pulse sequence was developed. The second method, reported in Chapter 2, involves a novel approach to the synthesis of secondary amines starting from reactive alkyl halides and azides. The convenient solid-phase protocol that was devised made use of the Staudinger reaction in order to accomplish highly efficient alkylations of N-alkyl phosphimines or N-aryl phosphimines with reactive alkyl halides. The second part of the thesis describes the design and synthesis of three classes of protease inhibitors targeting the cysteine proteases cathepsins S and K, and the serine protease hepatitis C virus (HCV) NS3 protease. Chapter 4 covers the design, solid-phase synthesis, and structure-activity relationships of 4-amidofurane-3-one P1-containing inhibitors of cathepsin S and the effects of P3 sulfonamide groups on the potency and selectivity towards related cathepsin proteases. This work resulted in the discovery of highly potent and selective inhibitors of cathepsin S. Two parallel solid-phase approaches to the synthesis of a series of aminoethylamide inhibitors of cathepsin K are presented in Chapter 5. Finally, Chapter 6 reports peptide-based HCV NS3 protease inhibitors containing a non-electrophilic allylic alcohol moiety as P1 group and also outlines efforts to incorporate this new template into low-molecular-weight drug-like molecules.

The asymmetric hydrogenation of olefins is a facile and popular method of reaching chiral products. Whereas ruthenium- and rhodium-catalyzed asymmetric hydrogenations have a long history, the use of iridium in this area is new but fast-growing. Since the first chiral N,P-ligated iridium catalyst was created in the late 1990s, the growing pool of N,P ligands has filled up rapidly, but most have been tested with a limited range of standard olefins. To extract the full potential of these complexes, new methods using substrates having many possible applications must be developed. This thesis focuses on the iridium-catalyzed asymmetric hydrogenation of three different new substrate classes to yield very high conversions and enantiomeric excesses (ee's). As the use of fluorine has recently become common in many different fields of chemistry, the asymmetric reduction of fluoroolefins to reach chiral products having fluorine at the stereogenic centers is highly interesting. We studied this reaction and eventually obtained very high ee values and lower degree of defluorination (Paper I and Paper II). The hydrogenations of trifluoromethylated olefins to reach products useful in applications reaching from pharmaceuticals to additives in liquid crystal displays (LCDs) were also challenging, but fruitful (Paper III). As asymmetric hydrogenation usually demands differences in the substituents of the double bond, the highly selective reduction of 1,1-diaryl olefins having similar aryls give a new perspective on the broad scope of substrates that N,P-ligated iridium complexes can reduce selectively (paper IV).

The aim of this thesis was to obtain a better understanding of the association between surfactants and biopolymers in bulk solutions and at solid/aqueous liquid interface. In order to do this, the interactions between surfactants and biopolymers were investigated with a variety of experimental techniques. The main focus has been on the interactions between fluorosurfactants and proteins, which are important during electrophoresis of proteins in silica capillaries. Electrophoretic separation of positively charged proteins is often complicated by non-specific adsorption of protein onto capillary wall, while it was found to improve when cationic fluorosurfactants were added into the background buffer. We investigated the interactions between a cationic fluorosurfactant, FC134, and a positively charged protein, lysozyme. By employing Nuclear Magnetic Resonance (NMR) and tensiometry we could conclude that the cationic fluorosurfactant did not associate with positively charged lysozyme in bulk solutions. At the solid/aqueous liquid interface, the adsorption of fluorosurfactants and lysozyme onto silica was studied by the surface force technique (MASIF), ellipsometry, reflectrometry, Quartz Crystal Microbalance (QCM-D) and Atomic Force Microscopy (AFM). Cationic fluorosurfactant FC134 was found to adsorb onto the silica surface in a form of bilayer aggregates, which led to a charge reversal of the originally negatively charged substrate. The adsorption of lysozyme onto silica was also extensive and it corresponded to the more than monolayer coverage. When adsorbing from mixed solutions, the presence of the cationic fluorosurfactant in the solution led to an elimination of the lysozyme in the resulting adsorbed layer. For the lysozyme concentration of 0.2 mg/ml, which is typical for the electrophoretic separation, it was found that adsorption of protein was suppressed by more than 90% when only 30 μM of FC134 was added into the buffer. The presence of the low amounts of residual proteins in the adsorbed layers caused an enhancement of the adsorption of fluorosurfactants, which was attributed to adsorption of the fluorosurfactants between proteins in a form of large vesicles. The interactions between a positively charged biopolymer chitosan and an anionic surfactant sodium dodecylsulfate (SDS) were studied with respect to the effect of the ionic strength of the background electrolyte, both in the bulk solution and at the silica/liquid interface. It was shown that SDS and chitosan form complexes in the bulk solution, which reverse their charge at higher SDS concentrations. At SDS concentrations above the critical micellar concentration, large aggregates were formed, which were trapped in long-lived nonequilibrium states at both high and low ionic strengths. SDS did not adsorb at the silica/liquid interface by itself. However, by employing QCM-D and ellipsometry we detected an extensive adsorption of SDS on the silica substrate, which has been modified by adsorbed chitosan. The structure of the chitosan layer on the lowly charged silica was strongly affected by the ionic strength of the solution from which the chitosan adsorption took place. The interactions between SDS and the pre-adsorbed chitosan were found to be similar on lowly charged silica and on highly charged mica. A novel method based on the Bruggeman effective medium approximation was proposed for the evaluation of ellipsometric data characterizing composite adsorbed layers. Finally, the effect of the adsorbed layer surface roughness on the QCM-D response in liquid was studied with focus on trapped water. It was found that QCM-D effectively senses water, which is mechanically trapped inside topographical structures with the size in nano-meter scale. / QC 20100809

Syftet med detta arbete har varit att försöka hitta alternativ till det kadmiumbase¬rade röda pigment som används idag. Detta har gjorts genom att delvis under¬söka kombinationer av grundämnen som i litteraturen finns omnämnda som röda glaspigment, delvis genom att försöka förbättra och underlätta produktionen av redan kända, men problematiska pigment. Det har konstaterats att det går att framställa ett rött glas när man smälter soda¬kalkglas med en kombination av molybden och selen, under reducerande beting¬elser. Rött glas med denna kombination har inte rapporterats tidigare. Pigmentet är känsligt för vilken glassammansättning man använder och flera vanliga glas¬komponenter måste undvikas. För att utvärdera färgen hos glasen användes UV/vis-spektroskopi och färgkoordinater i CIE-systemet. Både ESCA- och XANES-analyser visar att molybden finns i glaset som Mo6+joner. Färgen upp¬kommer troligtvis genom en interaktion mellan molybdenjonerna och selen i reducerad form. UV/Vis- och XANES spektra visar att selen finns i glaset i redu¬cerad form. Färgutvecklingen hos kopparrubinglas studerades med UV/vis-spektroskopi. Detta pigment behöver värmebehandlas för att färgen skall bildas. När låga vär¬mebehandlingstemperaturer och låga halter av de färgande komponenterna an¬vänds, är pigmentet stabilt under lång tid. Experimentella resultat från EXAFS- och TEM-analyser visar tydligt att färgkällan är metalliska kopparpartiklar i na¬nostorlek. Inverkan av olika reduktionsmedel på guld- och kopparrubinpigmenten har un¬dersökts. Det konstaterades att SnO är mer reducerande gentemot koppar än Sb2O3 i sodakalkglas. Kopparrubinglas kan framställas med bara endera av dessa reduktionsmedel, men SnO ger bättre resultat. Skift i absorbanstoppens läge och provets färg har observerats hos både guld- och kopparrubiner. Det största skiftet finns hos glas där en blåaktig ton erhållits. Skiftet beror troligtvis på att större partik¬lar bildats. Möjligheterna att kombinera röd färg med halvtransparenta alabasterglas har undersökts. Det konstaterades dock att alabastereffekten inte går att kombinera med pigment som kräver starkt reducerande miljöer. Både guld- och kopparrubiner är miljövänligare än det kadmiumbaserade pig¬mentet, och måste anses som möjliga alternativ. Mo/Se-pigmentet kan också vara ett alternativ. / The aim of this thesis has been to find alternatives in the alkali silicate glass system to the most commonly used red glass pigment today, which is based on Cd(S, Se). The overall strategy has been to facilitate the use of already existing, well known but complicated and control-demanding pigments. Also the possi¬bilities to obtain red glass by combining elements as briefly reported in litera¬ture as possible red glass pigments, has been investigated. It has been found that by combining molybdenum and selenium in alkali-lime-silica glass under reducing conditions, a red pigment can be obtained. Red glass originating from this combination has not been reported earlier. The pigment is sensitive to batch composition and some glass components must be avoided. UV/vis spec¬troscopy and CIE colour coordinates were used when colour of samples was evaluated. Both ESCA and XANES give evidence that molybde¬num is present as Mo6+ ions. The colour is caused by an interaction between the molybdenum ions and selenium under reducing conditions. The presence of se¬lenium in a reduced state is evidenced by UV/vis spectroscopy and XANES analysis. The colour development in copper ruby glasses was studied by UV/vis spectros¬copy. It was observed that when low concentrations of colouring components were used, the pigment is stable regarding colour over long periods of time. Ex¬peri¬mental results from TEM and EXAFS provided good evidence that the col¬our origi¬nates from nanoparticles of metallic copper. This is in analogy with the gold ruby pigment. The impact of different reducing agents on the copper and gold ruby pigments was examined. It was concluded that SnO has a stronger reducing capacity to¬wards copper than Sb2O3 in alkali silicate glasses. The copper ruby colour can be obtained by the use of one of these reducing agents solely. Shifts in absorbance peak position as well as in colour hues are observed in both pigments and the largest shifts in absorption are observed in blue or bluish glasses, probably caused by larger particles. The possibility to combine red colour and semi-transparent alabaster glasses was studied. The studies however, indicated that the alabaster effect is not compati¬ble with pigments requiring strongly reducing conditions. Both gold and copper rubies are more environmentally friendly than the cad¬mium based Cd(S, Se) pigment, and must be regarded as possible alternatives. The Mo/Se pigment can also be an alternative. / QC 20100820

This thesis concerns the study of D–π–A type dyes as sensitizers for NiO-based p-type dye-sensitized solar cells. The focus has been on the design and synthesis of efficient dyes and the identification of parameters limiting the solar cell performance. We have developed a new design strategy for the dyes: upon photoexcitation of the dye, the electron density is moving from the part that is attached to the semiconductor towards the part which is pointing away. This intramolecular charge transfer provides an efficient pathway for the following charge transfer processes. The first organic dye, composed of a triphenylamine (TPA) moiety as the electron-donor, dicyanovinyl groups as the electron-acceptors and linked by thiophene units, showed much better photovoltaic performance than other dyes reported at the same time, turning it into a model for future dye design. A series of dyes with different energy levels were synthesized and characterized on NiO-based devices using iodide/triiodide as redox couple. Lower photovoltaic performance was obtained for the dye with less negative reduction potential due to the insufficient driving force for dye regeneration. We have investigated the symmetric and unsymmetric structures of the dyes. The breaking of molecular symmetry did not significantly broaden the absorption spectrum, or improve the efficiency. In addition, we have tuned the molecular structure to prevent charge recombination. Increasing the distance between the anchoring group and the electron-acceptor was an effective way to improve the device efficiency. Besides TPA-based compounds, a zinc porphyrin dye was also synthesized and tested in p-type solar cells. However, the solar cell performed less well due to its narrow absorption band and the tendency for aggregation. Co-sensitization of the TPA-based dye with the porphyrin dye did not result in higher photovoltaic performance. After optimization of the dye structure, the highest overall conversion efficiency was achieved for the P5-sensitized solar cell, based on 1.5 μm NiO film prepared from NiCl2 and the F108 template precursor, and an acetonitrile-based electrolyte. / QC 20100909

This thesis deals with the synthesis and development of 18F-labelled alkyl etomidate and vorozole analogues, and their use as positron emission tomography (PET) tracers for the imaging of the steroid enzymes 11β-hydroxylase and aromatase. Two synthetic 18F-labelling approaches to the etomidate and vorozole analogues were developed, and the analogues were evaluated in some biological assays. The two-step labelling method was used to synthesise many compounds for biological evaluation. In the first step, a 18F-labelled intermediate based on a ditosylate or a halogenated diethyl ether was synthesised and used directly in the next alkylation step. The decay-corrected (d.c.) radiochemical yield was higher compared to other known two-step labelling methods. Once an appropriate candidate has been chosen for clinical evaluation, a one-step labelling method will be more suitable. We therefore developed a method based on precursors that had leaving groups at the end of their alkyl chains, and used these directly in the 18F-labelling synthesis. The one-step 18F-labelling synthesis required less reaction time and produced higher specific radioactivity and d.c. radiochemical yield than our two-step synthesis. With microwave heating, the reaction time was reduced to seconds and the d.c. radiochemical yield was better than that obtained with conventional heating. The one-step synthesis simplified the technical handling by allowing the tracer syntheses to be automated on the TRACERLab FXFN.

<p>In this thesis, synthesis of structures related to antifreeze glycoproteins (AFGPs) are presented. Synthetic routes to a protected carbohydrate derivative, 2,3,4,6-tetra-O-benzyl-β-galactopyranosyl-(1→3)-2-deoxy-2-azido-4,6-di-O-benzyl-β-D-thio-1-galactopyranoside, and a tBu-Ala-Thr-Ala-Fmoc tripeptide, are described. These compounds are meant to be used in the assembly of AFGPs and analogues thereof. A Gal-GlcN disaccharide was synthesized via glycosylation between the donor, bromo-2-O-benzoyl-3,4,6-tri-O-benzyl-α-Dgalactopyranoside, and acceptor, ethyl 4,6-O-benzylidene-2-deoxy-2-N-phthalimido-β-D-1-thio-glucopyranoside, using silver triflate activation. Subsequent epimerization to a Gal-GalN disaccharide was achieved using Moffatt oxidation followed by L-selectride® reduction. The tripeptide was synthesized in a short and convenient manner using solid phase peptide synthesis with immobilized Fmoc-Ala on Wang® resins as starting point.</p>

Ph.D. afhandling, Roskilde universitetscenter 2006.

Molecular mimics of PS II, which consist of a photosensitizer linked to electron acceptors/donors, are attractive candidates for the conversion of solar energy into chemical energy. Several different classes of sensitizers have been studied and among these, ruthenium(II) polypyridyl complexes continue to attract major attention. The first part of this thesis presents the photophysical properties, stereochemistry, and general synthesis of ruthenium(II) polypyridyl complexes based on 2,2´-bipyridyl and 2,2´:6´,2´´-terpyridyl ligands. The second part deals with ruthenium(II) polypyridyl complexes linked to electron acceptors (benzoquinone, naphthalene diimide) and electron donors (phenothiazine, tyrosine, manganese complexes). Functionalized 2,2´-bipyridines and 2,2´:6´,2´´-terpyridines were synthesized and used in the stepwise assembly of the chromophore-quencher complexes. These were fully characterized and the redox properties were studied by cyclic and differential pulse voltammetry. The intramolecular charge-separated states formed after light excitation of the ruthenium(II) unit were observed by time-resolved absorption and EPR spectroscopy. In the third part of this thesis, the synthesis and photophysical properties of a novel class of bistridentate ruthenium(II) polypyridyl complexes based on bipyridyl-pyridyl methane ligamds are discussed. The solution structures of the homoleptic and heteroleptic complexes were studied by 2D NMR techniques. The X-ray structure of one of the homoleptic complexes has been solved. The effect on the excited state lifetime for these ruthenium(II) complexes compared to the parent [Ru(tpy)2]2+ is discussed. Finally, in one of the heteroleptic complexes an interesting reversible linkage iomerization was observed that could be induced either electrochemically or chemically.