In this thesis, density functional theory is employed in the study of two kinds of systems that can be considered to be biomimetic in their own ways. First, three binuclear metal complexes, synthesized by the group of Prof. Ebbe Nordlander, have been investigated. The complexes are designed to resemble the active sites of phosphatase enzymes and have been examined in complexes where either two Zn(II) ions or one Fe(III) and one Mn(II) ion are bound. These dinuclear compounds were studied as catalysts for the hydrolysis of bis(2,4-dinitrophenyl) phosphate and the transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, which are model systems for the same reactions occurring in DNA or RNA. It was found that the two reactions take place in similar ways: a hydroxide ion that is terminally bound to one of the metal centers acts either as a nucleophile in the hydrolysis reaction or as a base in the transesterification. The leaving groups depart in an effectively concerted manner, and the formed catalyst-product complexes are predicted to be the resting states of the catalytic cycles. The rate-determining free energy barriers are identified from the catalyst-product complex in one catalytic cycle to the transition state of nucleophilic attack in the next. Another type of biomimetic modeling is made with an aim of imitating the conceptual features of selective binding of guests and screening them from solute-solvent interactions. Such features are found in so-called nanocontainers, and this thesis is concerned with studies of two capsules synthesized by the group of Prof. Julius Rebek, Jr. First, the cycloaddition of phenyl acetylene and phenyl azide has experimentally been observed to be accelerated in the presence of a capsule. Computational studies were herein performed on this system, and a previously unrecognized structure of the capsule is discovered. Two main factors are then identified as sources of the rate acceleration compared to the uncatalyzed reaction, namely the reduction of the entropic component and the selective destabilization of the reactant supercomplex over the transition state. In the second capsule study, the alkane binding trends of a water-soluble cavitand was studied. It is found that implicit solvation models fail severely in reproducing the experimental equilibrium observed between binding of n-decane by the cavitand monomer and encapsulation in the capsule dimer. A mixed explicit/implicit solvation protocol is developed to better quantify the effect of hydrating the cavitand, and a simple correction to the hydration free energy of a single water molecule is proposed to remedy this. The resulting scheme is used to predict new hydration free energies of the cavitand complexes, resulting in significant improvement vis-à-vis experiments. The computational results presented in this thesis show the usefulness of the quantum chemical calculations to develop understanding of experimental trends observed for substrate binding and catalysis. In particular, the methodology is shown to be versatile enough such that experimental observations can be reproduced for such diverse systems as studied herein. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.</p>

This thesis describes the design and synthesis of compounds that are intended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used N-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors. / <p>Report code: LIU-TEK-LIC-2006:45</p>

As of today, synthetic cannabinoids are one of the biggest groups of new psychoactive substances.These substances can be used as substitutes for the psychoactive drug cannabis, avoiding the legalrestrictions on cannabis. Furthermore, a variety of synthetic cannabinoids are synthesized with eithersignificant or very minor structural differences, making the detection of said novel drugs hard to keepup with and is therefore of great importance to have standards which help in the identification of theintake of the parent synthetic cannabinoid. In this project, several metabolites ofsynthetic cannabinoids with indole/indazole cores with differentside chains was synthesized. The general strategy used in this project was to N-alkylate the desiredcore followed by amide coupling with L-tert-leucine methyl ester or L-Valine methyl esterhydrochloride which resulted in 8 potential synthetic cannabinoid metabolites.

Most patients diagnosed with cancer will receive systematic chemotherapy at some point during their illness, which almost always cause severe side effects for the patients such as, anemia, nausea and vomiting. The problems with today’s chemotherapy is not only that it cause severe side effects, but also that the cancer may develop resistance to the therapy, which is why the development of a new type of therapeutic agent is in dire need. The ubiquitin proteasome system (UPS) is a vital machinery for the cancer cells to maintain protein homeostasis, which also make them vulnerable to any disruption of this system. In recent years, a new technology has been developed that utilize the UPS by chemically bringing an E3 ubiquitin ligase into close proximity of a protein of choice and tagging the protein with ubiquitin for degradation. This technology is called proteolysis targeting chimera (PROTAC). In this project, we managed to theoretically develop a new type of cancer therapeutic agent, that utilize the PROTAC system together with the first-in-class proteasome regulatory subunit, POH1, inhibitor Capzimin as a warhead. By using Capzimin as a warhead it should be possible to polyubiquitinate POH1, and thus induce proteotoxic stress in the cancer cells to trigger apoptosis. This theoretically developed drug is therefore called Capzimin-PROTAC, which should be able to trigger apoptosis in cancer cells, and at the same time being relatively safe to normal healthy cells.

Peptidoglycan (PGN) är en bakteriecellväggskomponent och känd för att känna igen olika receptorer eller enzymer för att leda aktiveringsimmunsystemet. Den allmänna strukturen för PGN består av sockerkedjor inklusive N-acetylglutamin (GlcNAc), N-acetylmuraminsyra (MurNAc) och tvärbundna peptidkedjor. PGN-fragment med D-Lac-ändpeptider har hittats från vankomycinresistenta enterokocker men ett kemiskt syntetiserat PGN-fragment med en D-Lac-ändpeptid har inte undersökts i detalj. Således fokuserade vi på syntesen av PGN-fragmentstrukturer som inkluderar en D-Ala-D-Lac-rest vid den terminala delen av peptidkedjan. För att syntetisera dessa fragmentstrukturer planerade vi att kombinera fastfassyntes (för Lac-peptiddelen) och lösningsfassyntes (för glykanberedning och kondensation). Detta tillvägagångssätt är fördelaktigt för framställning av peptidoglykanfragment med en komplex grenad peptiddel. Först beredde vi sockerdelen MurNAc-derivatet i lösningsfassyntes från ett glukosderivat. Medan den Lac-innehållande peptiden framställdes med fastfas-peptidsyntes med användning av 2-klortritylkloridharts. Med denna förening gav kondensationen av dessa två föreningar det önskade D-Lac-avslutade peptidoglykanfragmentet. / Peptidoglycan (PGN) is a bacterial cell wall component and known to be recognized by various receptors or enzymes to lead the activation immune system. The general structure of PGN consists of sugar chains including N-acetylglutamine (GlcNAc), N-acetylmuramic acid (MurNAc) and cross-linked peptide chains. PGN fragments having D-Lac terminus peptides have been found from vancomycin-resistant enterococcus, but a chemically synthesized PGN fragment having a D-Lac terminus peptide has not been examined in detail. Thus, we focused on the synthesis of PGN fragment structures that include a D-Ala-D-Lac residue at the terminal part of the peptide chain. In order to synthesize these fragment structures, we planned to combine solid-phase synthesis (for the peptide- Lac part) and solution-phase synthesis (for glycan preparation and the condensation). This approach is advantageous for the preparation of peptidoglycan fragments having complex branched peptide moiety. First, we prepared the sugar moiety MurNAc derivative in solution-phase synthesis from a glucose derivative. While, the Lac-containing peptide was prepared with solid-phase peptide synthesis using 2-chlorotrityl chloride resin. Having this compound, the condensation of these two compounds gave the desired D-Lac-terminated peptidoglycan fragment.

The application of different analytical techniques is fundamental in forensic drug analysis. In the wake of the occurrence of large numbers of new psychoactive substances possessing similar chemical structures as already known ones, focus has been placed on applied criteria for their univocal identification. These criteria vary, obviously, depending on the applied technique and analytical approach. However, when two or more substances are proven to have similar analytical properties, these criteria no longer apply, which imply that complementary techniques have to be used in their differentiation. This work describes the synthesis of some structural analogues to synthetic cannabinoids and cathinones based on the evolving patterns in the illicit drug market. Six synthetic cannabinoids and six synthetic cathinones were synthesized, that, at the time for this study, were not as yet found in drug seizures. Further, a selection of their spectroscopic data is compared to those of already existing analogues; mainly isomers and homologues. The applied techniques were mass spectrometry (MS), Fourier transformed infrared (FTIR, gas phase) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. In total, 59 different compounds were analyzed with the  selected techniques. The results from comparison of spectroscopic data showed that isomeric substances may in some cases be difficult to unambiguously identify based only on their GC-MS EI spectra. On the other hand, GC-FTIR demonstrated more distinguishable spectra. The spectra for the homologous compounds showed however, that the GC-FTIR technique was less successful compared to GC-MS. Also a pronounced fragmentation pattern for some of the cathinones was found. In conclusion, this thesis highlights the importance of using complementary techniques for the univocal identification of synthetic cannabinoids and cathinones. By increasing the number of analogues investigated, the more may be learnt about the capabilities of different techniques for structural differentiations, and thereby providing important identification criteria leading to trustworthy forensic evidence.

This thesis summarizes three novel and general reaction protocols for the synthesis of diaryliodonium salts. All protocols utilize mCPBA as oxidant and the acids used are either TfOH, to obtain triflate salts, or BF3•Et2O that gives the corresponding tetrafluoroborate salts in situ. Chapter two describes the reaction of various arenes and aryl iodides, delivering electron-rich and electron-deficient triflates in moderate to excellent yields. In chapter three, it is shown that the need of aryl iodides can be circumvented, as molecular iodine can be used together with arenes in a direct one-pot, three-step synthesis of symmetric diaryliodonium triflates. The final and fourth chapter describes the development of a sequential one-pot reaction from aryl iodides and boronic acids, delivering symmetric and unsymmetric, electron-rich and electron-deficient iodonium tetrafluoroborates in moderate to excellent yields. This protocol was developed to overcome mechanistic limitations existing in the protocols described in chapter two and three. The methodology described in this thesis is the most general, efficient and high-yielding existing up to date, making diaryliodonium salts easily available for various applications in synthesis.

Detta examensarbete beskriver optimering av ett katalytiskt protokoll för framställning av bisguaiacol F, ett ofarligt alternativ till bisphenol A. Lewissyrliga grupp IV metallkomplex med triflatligander användes som katalysatorer under milda betingelser och kinetisk analys användes för att underlätta optimeringen av reaktionsprotokollet för att öka utbyte och selektivitet för transformationen. Dessutom bidrog kinetiken med mekanistiska insikter och avslöjade att den nukleofila attacken starkt påverkar reaktionens selektivitet och utbyte. / This thesis describes the optimization of catalytic protocol for the formation of bisguaiacol F, a benign alternative to bisphenol A. Lewis acidic group IV metal complexes bearing triflate ligands were used as catalysts under mild conditions and kinetic analysis was used to aid optimization of the reaction protocol to increase the yield and selectivity of the transformation. In addition, the kinetics shed light on the operating mechanisms and revealed that competition of nucleophiles greatly impact selectivity and yield of the reaction.

Dynamic Combinatorial Chemistry (DCC) is a recently introduced supramolecular approach to generate dynamically interchanging libraries of compounds. These libraries are made of different building blocks that reversibly interact with one another and spontaneously assemble to encompass all possible combinations. If a target molecule, for instance a receptor is added to the system and one or more molecules show affinity to the target species, these compounds will, according to Le Châtelier´s principle, be amplified on the expense of the other non-bonding constituents. To date, only a handful of different systems and formats have been used. Hence, to further advance the technique, especially when biological systems are targeted, new reaction types and new screening methods are necessary. This thesis describes the development of reversible sulfur reactions, thiol/disulfide interchange and transthiolesterification (the latter being a new reaction type for DCC), as means of generating reversible covalent bond reactions. Two different types of target proteins are used, enzymes belonging to the hydrolase family and the plant lectin Concanavalin A. Furthermore, two new screening/analysis methods not previously used in DCC are also presented; the quartz crystal microbalance (QCM)-technique and catalytic self-screening. / QC 20101118

I rotaxaner följs förflyttningen av makrocykeln vanligtvis med 1H-NMR spektroskopi. Målet med detta projekt är i stället att utveckla ett system som möjliggör att förflyttningen av makrocykeln kan observeras med hjälp av luminiscerande lantanid emission. Detta bör vara ett kraftfullt verktyg, då luminiscerande emission skulle möjliggöra att makrocykelns position längs med tråden kan avläsas direkt med blotta ögat. För att lantanid-baserade system ska kunna luminiscera krävs det att en aktiverande antennmolekyl finns i närheten av lantaniden. I detta projekt placerades en lantanidligand i den ena stoppande änden av en [2]rotaxan och en antennmolekyl sattes på den trådade makrocykeln. En förändring av pH:t medför att makrocykeln förflyttas närmre till lantanidliganden, vilket i sin tur medför att antennen aktiverar lantaniden och den luminiscerande emissionen startar. Baserat på styrkan av luminiscensen bör man då kunna avgöra makrocykelns position i rotaxanen. I framtiden hoppas vi kunna använda detta visualiseringsverktyg för att kunna börja använda rotaxaner som biosensorer för medicinsk diagnostik. / In rotaxanes, the movement of the macrocycle is usually tracked using 1H-NMR spectroscopy. The goal of this project is to instead develop systems so one can follow the macrocycle movement through luminescent lanthanide emission. This should be a powerful tool, as luminescence emission would allow for a direct visual readout of the macrocycle position along the thread with the naked eye. To allow luminescence in lanthanide-based systems, a sensitizing antenna molecule needs to be present in close proximity to the lanthanide. In this project, a lanthanide ligand was placed at the stoppered end of a [2]rotaxane, and a sensitizing antenna was attached to the threaded macrocycle. A change in pH induces the macrocycle to move closer to the lanthanide stopper, which causes the antenna to sensitize the lanthanide and start the luminescence emission. Based on the strength of the luminescence, one should then be able to determine the location of the macrocycle in the rotaxane. We hope to use this visual readout tool to eventually turn rotaxanes into useful point-of-care biosensors for medical diagnostics.