This study addresses the issue of how to convert peptides into drug-like non- peptides with retained biological activities at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide. Knowledge of the bioactive conformations of endogenous peptides is invaluable for the conversion of peptides into less peptidic analogues. Effectively constrained cyclic analogues, with retained pharmacological activities, may provide valuable information about the bioactive conformations of the peptide in question. This thesis describes the development of synthesis for a number of protected, aldehyde-functionalized building blocks for standard solid phase peptide synthesis, and their use for the preparation of cyclic peptide analogues. The effect of variations in the side-chain lengths of the building blocks, on the outcome of the cyclizations was studied. Incorporation of a building block derived from L-aspartic acid afforded bicyclization towards the C-terininal end of the peptide, while for the corresponding L-glutamic acid derived building block, N-terminal directed bicyclization was achieved. A building block derived from L-2-aminoadipic acid was exploited for monocyclization furnishing cis- and trans- vinyl sulfide bridged peptide analogues. The described cyclization methods have been applied to the synthesis of a number of conformationally constrained Ang II analogues, for which the pharmacological properties have been evaluated. Two of the Ang II analogues synthesized displayed high affinities and full agonist activities at the AT1 angiotensin receptor, and have proven to be useful tools in the search for the bioactive conformation of Ang II.

Today, the demand for speed in drug discovery is constantly increasing, particularly in the iterative processes of hit validation and expansion and lead optimization. Irradiation with microwaves (MWs) has been applied in the area of organic synthesis to accelerate chemical reactions and to facilitate the generation of new chemical entities since 1986. In the work presented in this thesis, the use of MW-mediated heating has been expanded to address three fields of drug discovery, namely hit expansion, chemical library generation and genomics. In the first project, potential inhibitors of malaria aspartic proteases were designed and synthesized, partly by MW-assisted organic chemistry, and evaluated with regard to their inhibitory efficacy on five malaria aspartic proteases and their selectivity over two human aspartic proteases. The synthetic work included the development of fast and convenient methods of MW-assisted formation of thiazolidines and epoxy esters. Some of the resulting structures proved to be efficacious inhibitors of the aspartic protease that degrades haemoglobin in all four malaria parasites infecting man. No inhibitor affected the human aspartic proteases. Expedient, two-step, single-operation synthetic routes to heterocycles of medicinal interest were developed in the second and third projects. In the former, the use of a versatile synthon, Ph3PCCO, provided α,β-unsaturated lactones, lactams and amides within 5–10 minutes. In the latter project, saturated lactams were formed from amines and lactones in 35 minutes, in the absence of strong additives. These two MW-mediated protocols allowed the reduction of the reaction time from several hours or days to minutes. In the fourth project, a fully automated MW-assisted protocol for the important enzyme-catalysed polymerase chain reaction (PCR) was established. In addition, the PCR reaction could be performed in unusually large volumes, 2.5 mL and 15 mL, with yields corresponding to those from conventional PCR. Good amplification rates suggested that the thermophilic enzyme, Taq polymerase, was not affected by the MW radiation.

New strategies are needed to counter the growing problem of bacterial resistance to antibiotics. One such strategy is to design compounds that target bacterial virulence, which could work separately or in concert with conventional bacteriostatic or bactericidal antibiotics. Pilicides are a class of compounds based on a ring-fused 2-pyridone scaffold that target bacterial virulence by blocking the chaperone/usher pathway in E. coli and thereby inhibit the assembly of pili. This thesis describes the design, synthesis, and biological evaluation of compounds based on the pilicide scaffold with the goal of improving the pilicides and expanding their utility. Synthetic pathways have been developed to enable the introduction of substituents at the C-2 position of the pilicide scaffold. Biological evaluation of these compounds demonstrated that some C-2 substituents give rise to significant increases in potency. X-ray crystallography was used to elucidate the structural basis of this improved biological activity. Furthermore, improved methods for the preparation of oxygen-analogues and C-7 substituted derivatives of the pilicide scaffold have been developed. These new methods were used in combination with existing strategies to decorate the pilicide scaffold as part of a multivariate design approach to improve the pilicides and generate structure activity relationships (SARs). Fluorescent pilicides were prepared using a strategy where selected substituents were replaced with fluorophores having similar physicochemical properties as the original substituents. Many of the synthesized fluorescent compounds displayed potent pilicide activities and can thus be used to study the complex interactions between pilicide and bacteria. For example, when E. coli was treated with fluorescent pilicides, it was found that the compounds were not uniformly distributed throughout the bacterial population, suggesting that the compounds are primarily associated to bacteria with specific properties. Finally, by studying compounds designed to inhibit the aggregation of Aβ, it was found that some compounds based on the pilicide scaffold inhibit the formation of the functional bacterial amyloid fibers known as curli; these compounds are referred to as 'curlicides'. Some of the curlicides also prevent the formation of pili and thus exhibit dual pilicide-curlicide activity. The potential utility of such 'dual-action' compounds was highlighted by a study of one of the more potent dual pilicide-curlicides in a murine UTI model were the compound was found to significantly attenuate virulence in vivo.

This thesis describes novel reaction protocols for the synthesis of diaryliodonium salts and also provides an insight to the mechanism of α-arylation of carbonyl compounds with diaryliodonium salts.  The first chapter gives a general introduction to the field of hypervalent iodine chemistry, mainly focusing on recent developments and applications of diaryliodonium salts. Chapter two describes the synthesis of electron-rich to electron-poor diaryliodonium triflates, in moderate to excellent yields from a range of arenes and iodoarenes. In chapter three, it is described that molecular iodine can be used together with arenes in a direct one-pot, three-step synthesis of symmetric diaryliodonium triflates. A large scale synthesis of bis(4-tert-butylphenyl)iodonium triflate is also described, controlled and verified by an external research group, further demonstrating the reliability of this methodology. The fourth chapter describes the development of a sequential one-pot synthesis of diaryliodonium salts from aryl iodides and boronic acids, furnishing symmetric and unsymmetric, electron-rich to electron-poor diaryliodonium tetrafluoroborates in moderate to excellent yields. This method was developed to overcome the regiochemical limitations imposed by the reaction mechanism in the protocols described in the preceding chapters. Chapter five describes a one-pot synthesis of heteroaromatic iodonium salts under similar conditions described in chapter two. The final chapter describes the reaction of enolates with chiral diaryliodonium salts or together with a phase transfer catalyst yielding racemic products. DFT calculations were performed, which revealed a low lying energy transition state (TS) between intermediates, which is believed to be responsible for the lack of selectivity observed in the experimental work. It is also proposed that a [2,3] rearrangement is preferred over a [1,2] rearrangement in the α-arylation of carbonyl compounds. The synthetic methodology described in this thesis is the most generally applicable, efficient and high-yielding to date for the synthesis of diaryliodonium salts, making these reagents readily available for various applications in synthesis.

The major part of this thesis describes the asymmetric synthesis of β- and γ-amino alcohols through the combination of ruthenium catalyzed racemization and enzymatic kinetic resolution. The dynamic kinetic resolution, DKR, protocol for chlorohydrins was improved by employing Bäckvall’s catalyst, which is a base activated racemization catalyst, in combination with Burkholderia cepacia lipase. These optimized conditions broadened the substrate scope and improved the yields and ee’s of the obtained chlorohydrin acetates. The utility of the method was demonstrated in the synthesis of (S)-salbutamol. In the second part of the thesis, DKR was utilized in the enantio-determining step of the total synthesis of (R)-duloxetine. Optimized DKR conditions, combining Bäckvall’s catalyst together with Candida antarctica lipase B, afforded a β-cyano acetate in high yield and ee. (R)-Duloxetine was accessible through synthetic alterations of the enantioenriched β-cyano acetate in high overall yield. A dynamic kinetic asymmetric transformation, DYKAT, protocol to obtain enantio- and diastereomerically pure γ-amino alcohols was developed. In a first step N-Boc-aminoketones were obtained in high enantiomeric purity through a proline-catalyzed Mannich reaction. Subsequent in situ reduction coupled with a highly efficient DYKAT yielded γ-amino acetates in high dr and ee. The γ-amino alcohols were available through simple hydrolysis/deprotection with retained stereochemistry. In the final part of the thesis a heterogeneous bifunctional catalytic system is reported, which combines the catalytic properties of transition metal-catalyzed racemization with enzymatic acylation. A novel ruthenium-phosphonate complex was synthesized and then covalently anchored to the active site of solid supported Candida antarctica lipase B. The partially inhibited beads proved to be catalytically active both in racemization as well as enzymatic acylation. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Epub ahead of print.

En förhöjd produktion av fria kappakedjor (KFLC) i serum observeras vanligen vid inflammatoriska processer och vid autoimmuna sjukdomar. En överproduktion av fri kappakedja utgör en markör för intratekal immunglobulinproduktion i centrala nervsystemet (CNS) vilket kan ofta ses vid multipel skleros och andra inflammatoriska nervsjukdomar. Detta kan mätas både kvantitativt genom IgG index med nefelometri och kvalitativt genom att påvisa oligoklonala band i cerebrospinalvätska (CSV) med isoelektrisk fokusering. Syftet med studien är att sätta upp analys för bestämning av fri kappa-kedja i likvor på en nefelometer och utvärdera olika kvantitativa mått för intratekal Ig-syntes där fri kappakedja ingår genom att jämföra de mot isoelektrisk fokusering, vilket är dagens standardmetod för att påvisa intratekal Ig syntes. Studien erhöll goda resultat för olika KFLC parametrar jämfört med oligoklonalaband, där KFLC IF påvisade högst sensitivitet och specificitet (72% och 93%) jämfört med oligoklonala band. / An increased production of free coat chains in (KFLC) serum is commonly observed in inflammatory processes and in autoimmune diseases. An overproduction of free kappa chain is a marker for intrathecal immunoglobulinproduction in the central nervous system (CNS), which can often be seen in multiple sclerosis and other inflammatory nerve diseases. This can be measured both quantitatively by IgG index with nephelometry and qualitatively by detecting oligoclonal bands in cerebrospinal fluid (CSF) with isoelectric focusing. The purpose of the studies is to set up analysis for determination of free kappa chain in liquids on a nephelometer and evaluate different quantitative measures for intrathecal Ig synthesis where free kappa chain is included by comparing them against isoelectric focusing, which is the current standard method for detecting intrathecal Ig synthesis. The study obtained good results for different KFLC parameters compared to oligoclonal bands, where KFLC IF has the highest sensitivity and specificity (72%and 93%) compared to oligoclonal bands.

In recent years, texture synthesis has been a heated topic in computer graphics, and the development of advanced algorithms for generating high-quality 3D textures is an area of active research. A recently proposed model, Neural Cellular Automata, can synthesize realistic 2D texture images or videos. However, due to the complexity and non-differentiable nature of 3D rendering and the lack of definition of the neighborhood on 3D mesh objects, no one has extended the 2D Neural Cellular Automata to the 3D scenario. In this master’s thesis, we propose a novel method for modeling the neighborhood relationship on 3D mesh objects, drawing inspiration from a graph variant of the Neural Cellular Automata. We also design an end-to-end 3D texture synthesis pipeline, leveraging a differentiable renderer to enable the Graph Neural Cellular Automata to learn to synthesize desired 3D textures. Our method allows users to either give the text description of the target textures or present the target texture images as the objectives. We evaluate the effectiveness of our proposed method both qualitatively and quantitatively, comparing it with the state-of-the-art method to demonstrate that it achieves comparable or better results. Furthermore, we explore the homology between the graph variant of Neural Cellular Automata and the 2D model, examining whether our proposed model preserves critical properties of the 2D model such as zero-shot generalization and self-regeneration. Finally, we analyze the limitations and potential drawbacks of our proposed method and suggest directions for future research. In summary, this thesis proposes a novel approach to synthesizing high-quality 3D textures using the Graph Neural Cellular Automata model and a differentiable renderer. Our work provides a foundation for future research in this area, and we believe that our findings will contribute to the development of advanced algorithms for 3D texture synthesis. / Under de senaste åren har textursyntes varit ett hett ämne inom datorgrafik, och utvecklingen av avancerade algoritmer för att generera högkvalitativa 3D-texturer är ett aktivt forskningsområde. En nyligen föreslagen modell, Neural Cellular Automata, kan syntetisera realistiska 2D-texturbilder eller videor. Dock, på grund av komplexiteten och den icke-differentierbara naturen av 3D-rendering och bristen på definition av grannskapet på 3D-meshobjekt, har ingen utvidgat 2D Neural Cellular Automata till 3D-scenariot. I den här masteruppsatsen föreslår vi en ny metod för att modellera grannskapsrelationen på 3D-meshobjekt, inspirerade av en grafvariant av Neural Cellular Automata. Vi utformar också en ände-till-ände 3D-textursyntes pipeline, genom att utnyttja en differentierbar renderer för att möjliggöra för Graph Neural Cellular Automata att lära sig syntetisera önskade 3D-texturer. Vår metod tillåter användare att antingen ge textbeskrivningen av måltexturerna eller presentera måltexturbilderna som målen. Vi utvärderar effektiviteten av vår föreslagna metod både kvalitativt och kvantitativt, jämför den med den mest avancerade metoden för att visa att den uppnår jämförbara eller bättre resultat. Dessutom utforskar vi homologin mellan grafvarianten av Neural Cellular Automata och 2D-modellen, undersöker om vår föreslagna modell bevarar kritiska egenskaper hos 2D-modellen som zero-shot generalisering och självregenerering. Slutligen analyserar vi begränsningarna och eventuella nackdelar med vår föreslagna metod och föreslår riktningar för framtida forskning. Sammanfattningsvis föreslår denna avhandling en ny metod för att syntetisera högkvalitativa 3D-texturer med hjälp av Graph Neural Cellular Automata-modellen och en differentierbar renderer. Vårt arbete ger en grund för framtida forskning inom detta område, och vi tror att våra fynd kommer att bidra till utvecklingen av avancerade algoritmer för 3D-textursyntes.

As an innovation Evidence-Based Practice (EBP) is designed as a tool for clinical problem solving. According to its theory of use EBP will bring a difference for policy makers, for professionals, for researchers and for service users. One question to be asked is whether EBP actually leads to the radical social change it is designed to accomplish. The aim of the study is to describe and analyse the outcome of the effort to establish EBP, with a focus on the case of social work in Sweden. The research questions are: What is EBP? Why are efforts made to establish EBP? What is the outcome of the EBP project? How can the outcome of the EBP project be explained? The case study was conducted on a critical realistic meta-theoretical ground with a focus on explanation of social change with an explicit actor-structure perspective. Methodologically, a narrative synthesis of studies was made. As a complement primary data were collected to fill empirical gaps. The state of things was described before and after the EBP-initiatives. Several helping theories – Kuhn’s theory of paradigm, program theory, neo-institutional theory and theory of diffusion – were used to analyse the empirically mapped outcome of the EBP project. The results show that the import of the original model of Evidence-Based Medicine (EBM) to social work is a part of a wider social movement in the helping and educational professions. The new model has influenced social work as a discipline, as a field of practice and as a field of policy. There are examples of full-scale implementations of EBP, although EBP has not reached a general status as daily practice. Some obstacles remain. The gradual adaption of EBP corresponds to criteria hold by Kuhn for a paradigm shift. Acceptance of the model has contributed to change the structure and function of social systems. At an organizational level, this change means on-going institutionalization. The innovation is influencing the way institutional actors conduct their work. Although the structural conditions have been optimal, the EBP-model has been debated with heat. The EBP-debate and policy-driven infrastructural efforts have brought a more in-depth examination of the model. So-called coercive, normative, and regulative isomorphisms were used to change organizations. The degree of institutionalization depended on the individuals and the organizations willingness and preparedness to change, to understand, and to put the model into practice. When actors used a less strict version of the original EBP model, the pace of cultural and institutional change slowed down.

As an innovation Evidence-Based Practice (EBP) is designed as a tool for clinical problem solving. According to its theory of use EBP will bring a difference for policy makers, for professionals, for researchers and for service users. One question to be asked is whether EBP actually leads to the radical social change it is designed to accomplish. The aim of the study is to describe and analyse the outcome of the effort to establish EBP, with a focus on the case of social work in Sweden. The research questions are: What is EBP? Why are efforts made to establish EBP? What is the outcome of the EBP project? How can the outcome of the EBP project be explained? The case study was conducted on a critical realistic meta-theoretical ground with a focus on explanation of social change with an explicit actor-structure perspective. Methodologically, a narrative synthesis of studies was made. As a complement primary data were collected to fill empirical gaps. The state of things was described before and after the EBP-initiatives. Several helping theories – Kuhn’s theory of paradigm, program theory, neo-institutional theory and theory of diffusion – were used to analyse the empirically mapped outcome of the EBP project. The results show that the import of the original model of Evidence-Based Medicine (EBM) to social work is a part of a wider social movement in the helping and educational professions. The new model has influenced social work as a discipline, as a field of practice and as a field of policy. There are examples of full-scale implementations of EBP, although EBP has not reached a general status as daily practice. Some obstacles remain. The gradual adaption of EBP corresponds to criteria hold by Kuhn for a paradigm shift. Acceptance of the model has contributed to change the structure and function of social systems. At an organizational level, this change means on-going institutionalization. The innovation is influencing the way institutional actors conduct their work. Although the structural conditions have been optimal, the EBP-model has been debated with heat. The EBP-debate and policy-driven infrastructural efforts have brought a more in-depth examination of the model. So-called coercive, normative, and regulative isomorphisms were used to change organizations. The degree of institutionalization depended on the individuals and the organizations willingness and preparedness to change, to understand, and to put the model into practice. When actors used a less strict version of the original EBP model, the pace of cultural and institutional change slowed down.

In novel drug delivery system, the encapsulation of therapeutic cells in microparticles has great promises for the treatment of a range of health con- ditions. Therefore, the encapsulation material and technology are of great importance to the validity and efficiency of the advanced medical therapy. Several unsolved challenges in regards to versatile microparticle synthesis ma- terials and methods form the main obstacle for a translation of novel cell therapy concepts from research to clinical practice. Thiol-ene based polymer systems have emerged and gained great popular- ity in material development in general and in biomedical applications specif- ically. The thiol-ene platform is broad and therefore of interest for a variety of applications. At the same time, many aspects of this material platform are largely unexplored, for example material and manufacturing technology developments for microfluidic applications . In this Ph.D. thesis, thiol-ene materials are explored for use in cell encap- sulation. The marriage of these two technology fields breeds the possibility for a novel microfluidic cell encapsulation approach using a novel encapsulation material. To this end, several new manufacturing technologies for thiol-ene and thiol-ene-epoxy droplet microfluidic devices were developed. Moreover, core-shell microparticle synthesis for cell encapsulation based on a novel co- synthesis concept using a thiol-ene based material was developed and inves- tigated. Finally, a thiol-ene-epoxy system was also used for the formation of microwells and microchannels that improve protein analysis on microarrays. The first part of the thesis presents the background and state-of-the-art technologies in regards to cell therapy, microfluidics, and thiol-ene based ma- terials. In the second part of the thesis, a novel manufacturing approach of thiol-ene-epoxy material as well as core-shell particle co-synthesis in micro- fluidics using thiol-ene based material are presented and characterized. The third part of the thesis presents the cell viability studies of encapsulated cells using the novel encapsulation material and method. In the final part of the thesis, two applications of thiol-ene-epoxy gaskets for protein detection mi- croarrays are presented. / Inkapsling av levande celler i mikrokapslar för terapeutiska ändamål är mycket lovande för frmatida behandling av många olika sjukdomar. Emeller- tid är en behandlings effektivitet i hög grad beroende av vilka material som används för inkapsling och vilken teknisk lösning som används för att ska- pa mikrokapslarna. För närvarande återstår det många utmaningar för att omvandla grundforskningresultat till klinisk verklighet, vilken kräver mer än- damålsenliga tillvägagångssätt för att tillverka mikrokapslar i material som är kompatibla med användningsområdena. De senaste åren har tiol-en baserade polymerer har blivit mycket använda för materialutveckling i stort och för biomedicinska tillämpningar i synnerhet. Med tiol-en kemi kan en mycket stor mängd helt olika syntetiska material framställas, vilket gör tiol-ener intressanta för en mängd applikationer. För närvarande är dock mycket inom denna materialklass outforskat, t.ex. inom material och tillverkningmetodik för mikrofluidiktillämpningar. I denna avhandling används tiol-ener för cellinkapsling. Sammanslagning av dessa teknologier möjliggör en ny typ av cellinkapsling med nya materi- alegenskaper. En mängd olika tillverkningssätt där tiol-en eller tiol-en-epoxi används för droplet-mikrofluidiksystem utvecklades. Core-shell mikrokapsel- syntes för cell-inkapsling baserat på en ny metod för samtidig syntes av både core och shell utvecklades och karaktäriserades. Slutligen utvecklades ett tiol- en-epoxi system för enkel integrering med proteinmikroarrayer på objektsglas. I avhandlingens första del presenteras bakgrund och dagens bästa teknolo- gier för terapeutisk cellinkapsling, mikrofluidik och tiol-en baserade material. I avhandlingens andra del presenteras en ny tillverkningsmetod för mikro- strukturerade tiol-en-epoxi artiklar och samtidig syntes av core och shell för mikrokapslar med användande av mikrofluidik. I den tredje delen presenteras cellöverlevandsstudier för de celler som inkapslats med de nya materialen och de nyutvecklade metoderna. I den avslutande delen beskrivs två specifika fall där tiol-en-epoxi komponenter används för proteindetektion och mikroarrayer. / <p>QC 20171122</p>