<p>Abnormal aggregation of misfolded proteins is related to numerous neurodegenerative diseases, which include Alzheimer’s, Parkinson’s disease and prion diseases. Luminescent conjugated probes (LCPs) have been used as dyes for these supramolecular assemblies termed amyloid fibrils. To these probes, metalloporphyrin (MP) derivates have been attached to achieve new spectroscopic properties, which will allow for new ways to study protein aggregation diseases.</p><p>In this thesis the synthesis of two different LCPs anchored porphyrin derivates are described. The LCPs are synthesized from 3-thiopheneacetic acid and additional thiophene units are added with the use of Suzuki cross coupling reaction. The porphyrin is synthesized from pyrrol, benzaldehyde and methyl-4- formylbenzoate in a condensation reaction. In the first target molecule (TM) the porphyrin and thiophene are coupled with a spacer and the second one is a direct coupling between the two compounds.</p>

Abnormal aggregation of misfolded proteins is related to numerous neurodegenerative diseases, which include Alzheimer’s, Parkinson’s disease and prion diseases. Luminescent conjugated probes (LCPs) have been used as dyes for these supramolecular assemblies termed amyloid fibrils. To these probes, metalloporphyrin (MP) derivates have been attached to achieve new spectroscopic properties, which will allow for new ways to study protein aggregation diseases. In this thesis the synthesis of two different LCPs anchored porphyrin derivates are described. The LCPs are synthesized from 3-thiopheneacetic acid and additional thiophene units are added with the use of Suzuki cross coupling reaction. The porphyrin is synthesized from pyrrol, benzaldehyde and methyl-4- formylbenzoate in a condensation reaction. In the first target molecule (TM) the porphyrin and thiophene are coupled with a spacer and the second one is a direct coupling between the two compounds.

<p>2,6-Disubstituted spiro[3.3]heptanes were synthesized to investigate and develop synthetic methods for preparation of these compounds. Possibilities for introducing different functionalities like nitriles and sulfonamides were also investigated.</p><p> </p><p>Synthetic routes presented describe successive [2+2] cycloadditions between dichloroketene and olefins to give the sought after spiro compounds with low to moderate yields throughout the multi-step synthesis. [2+2] Cycloadditions offered low turnovers and chromatography was required for purification.</p><p> </p><p>A synthetic route with cyclisations through double substitution reactions between di-electrophiles and di-nucleophiles resulting in a 2,6-disubstituted spiro[3.3]heptane is also described. This multi-step synthesis offered higher turnover and yields and often there was no need for purification through chromatography.</p>

<p>This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an <em>N</em>-acyl-(4<em>R</em>)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated.</p> / Report code: LIU-TEK-LIC-2006:46.

This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated. / Report code: LIU-TEK-LIC-2006:46.

The development of a synthetic method of radiolabelled methylphosphono-fluoridates on a milligram scale is presented. The aim of this method is, besides affording high yield, to choose reaction pathways and reagents so that handling and transfer of labelled toxic substances is minimised, thereby reducing the risk of exposure as much as possible. The only substituent that is stable enough to be labelled is the methyl group, directly bonded to phosphorus. A drawback when labelling the methyl group is that it requires the label to be introduced early in the synthesis since the carbon-phosphorus bond of the methyl substituent usually has to be synthesized a few steps ahead of the final product. Two new classes of reagents for halogenation of phosphorus oxyacids have been developed. Firstly, four different analogues of α-chloroenamines and α-fluoroenamines were evaluated. Secondly, cyanuric fluoride was assessed in solution, but more importantly, as a resin-bound reagent. The reagents are evaluated for halogenation of phosphinic, phosphonic and phosphoric acids. Cyanuric fluoride is also successfully loaded on a polystyrene resin and used as a solid-phase reagent. The reagents produce high yields and low levels of impurities on a milligram scale. Furthermore, a new method for the preparation of mono-alkylated phosphonic acids on a small scale has been developed. The new method utilises the crystal water bound to certain salts to liberate limited amounts of water in a controlled manner. Phosphonic dichlorides are in this way reacted with water to form anhydrides. The anhydride is then cleaved with an appropriate alcohol to produce mono-alkylated phosphonic acids. / Rikard Norlin = Rikard Wärme

Photoredox catalysis applications for the purpose of new synthetic routes in organic and sustainable chemistry are hot topics in organic synthesis today. In the present study, the synthesis of a chiral proline-based organocatalyst functionalized with 10-phenyl-10H phenothiazine (PTH) photocatalytic moietiesis investigated and attempted for the first time. PTH, an organic photocatalyst, isstudied for its photocatalytic activity in different organic reactions, such as dehalogenation of aromatic halides and the pinacol coupling reaction between aromatic aldehydes. These transformations are otherwise difficult to achieve without a suitable catalyst and the reactions were performed with moderate to high yields. / Applikationer av photoredox-katalys med syftet att generera nya syntetiska vägar inom organisk och hållbar kemi är populära ämnen i organisk syntes idag. I denna studien undersöktes för första gången syntesen av en kiral prolinbaserad organokatalysator som är funktionaliserad med fotokatalytiska enheter (10-fenyl-10H-fenotiazin (PTH)). Den fotokatalytiska aktiviteten av PTH studerades för olika organiska reaktioner, såsom t.ex. dehalogenering av aromatiska halider och pinacolkopplingar mellan aromatiska aldehyder. Dessa transformationer är annars svåra att uppnå utan en lämplig fotokatalysator och reaktionerna utfördes med måttliga till höga utbyten.

<p>Bicyclic dihydrothiazolo fused 2-pyridones have been studied as a new class of antibacterial agents, termed pilicides, that target the formation of adhesive bacterial surface organelles (pili) in pathogenic bacteria. Synthetic methods to further functionalize the bicyclic 2-pyridone scaffold have been developed in order to increase water-solubility and thereby facilitate biological evalua-tions. This was accomplished by introducing aminomethylenes at the open position C-6. Tertiary amines were introduced via a microwave–assisted Mannich reaction and a synthetic route based on a formyl intermediate gave access to primary, secondary and tertiary amines, but also to other interesting functionalities. Biological evaluation confirmed that several of the function-alized compounds inhibited pili formation in uropathogenic <i>E. coli</i>., as dem-onstrated by assays of hemagglutination, biofilm formation and adherence to bladder cells. Co-crystallizing one of the pilicides with the target protein gave information about the binding site and based on this a mechanism of action was proposed, which was supported experimentally by surface plas-mon resonance and single point mutations in the protein.</p><p>Furthermore, the previously developed acylketene imine reaction used to prepare bicyclic thiazolo fused 2-pyridone pilicides has been developed to allow preparation of other ring-fused 2-pyridone systems. Benzo[a]quinolizine-4-ones and indolo[2,3-a]quinolizine-4-ones could be prepared in a fast and simple manner starting from dihydroisoquinolines and a β-carboline. Finally, this method could also be applied for the preparation of heteroatom analogs of the previously studied sulfur containing pilicides. Biological evaluations established that the sulfur atom can be replaced by oxygen and still maintain the ability to prevent pili assembly.</p>

<p>This thesis describes the design and synthesis of compounds that are</p><p>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 <em>N</em>-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

Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.