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The construction of duocarmycin-like compounds is often associated with lengthy synthetic routes. Presented herein is the development of a short and convenient synthesis of a type of duocarmycin prodrug. The 1,2,3,6-tetrahydropyrrolo[3,2-e]indole-containing core is here constructed from commercially available Boc-5-bromoindole in four steps and 23% overall yield, utilizing a Buchwald-Hartwig amination followed by a sodium hydride-induced regioselective bromination. In addition, protocols for selective mono- and di-halogenations of positions 3 and 4 were also developed, which could be useful for further exploration of this scaffold.

Genom att sänka ett företags kapitalbindning och höja dess leveransprecision kan det bli mer konkurrenskraftigt. Denna studie baseras på ett fallföretag som vill sänka sitt bundna kapital och som har en leveransprecision på 14%. Syftet med denna studie är att se vilka brister som finns i deras nuvarande arbetssätt för planering samt vad dessa brister leder till med målet att ta fram förslag på hur dessa brister kan motverkas och uppskatta vad effekten blir. Fallföretagets problemområden: Planeringsmetoder och följden av de nuvarande metoderna. Isolationen mellan fallföretagets avdelningar. Bristen på insikt i sin egen kapacitet. En komplex planeringssituation till följd av en produktion med många delprocesser och mycket variation. Efter analys av insamlad data och deras nuvarande metoder så har förbättringsförslag tagits fram för att fallföretaget ska göra rätt med planeringen från start istället för att ständigt förändra produktionsplanen. Detta uppskattas leda till en ökning av leveransprecisionen till 70-80% samt en sänkning av kapitalbindningen med 35-40%.

Sammanfattning Bakgrund: Härlett ur finansiella skandaler har revisorns oberoende i allmänhet ifrågasatts och som åtgärd har EU-kommissionen via ett revisionspaket påfört regler om tvingande byrårotation för företag av allmänt intresse. Den relationella uppdragstiden mellan revisionsbyråer och klienten har således tidsbegränsats. Härav följer diskussioner såväl inom revisionsbranschen som inom litteraturen kring huruvida en sådan tidsbegränsning kommer påverka revisionskvaliteten. I samma diskussioner förekommer inte bara uttalanden om revisorns faktiska och synbara oberoende då även revisorns kompetens diskuteras som beroende faktorer till revisionskvaliteten. Uppsatsen kommer därmed beakta såväl faktiska som synbara aspekter kring begränsade uppdragstiders påverkan på revisionskvaliteten. Syfte: Uppsatsen syftar till att komplettera redan befintliga diskussioner inom det vetenskapliga forskningsområdet som berör uppdragstiders påverkan på revisionskvaliteten. Syftet uppfylls genom att på byrånivå studera hur begränsade uppdragstider påverkar revisionskvaliteten ur såväl faktiska som synbara aspekter. Metod: Multipel logistisk regression kommer analysera insamlad data från årsredovisningar och revisionsberättelser mot faktisk revisionskvalitet. Samtidigt har en enkät utformats, vilken avser att studera tredje parts uppfattning kring synbar revisionskvalitet. Teorikapitlet kommer ligga till grund för såväl definitioner som analyser. Slutsatser: Via analysen av uppsatsens resultat för såväl den faktiska revisionskvaliteten som för den synbara revisionskvaliteten tillåts en samlad slutsats kring total revisionskvalitet. Vad avser faktisk revisionskvalitet ses inte uppdragstidens längd på byrånivå ha någon signifikant påverkan på revisionskvaliteten. Därav förmodas inte revisorns oberoende eller kompetens beröras nämnvärt av lagändringen. Dock diskuteras en indirekt påverkan på revisorns faktiska oberoende varför faktisk revisionskvalitet ändock torde anses positivt på, Background: Derived from financial scandals the independence of the auditor has publicly been questioned and as a result the EU Commission regulated mandatory audit-firm rotation for public companies. Thus, the audit firm and client relationship has been limited. Hence, discussions within the accountancy profession as well as within the literature surrounding the possible effects the change in regulation might have on audit quality. Not only statements surrounding the auditors’ independence of mind and independence in appearance occur in these discussions but also the competence of the auditor as a dependent factor to audit quality. The paper will hereby consider quality aspects in fact as well as in appearance related to mandatory audit-firm rotation and its impact on audit quality. Purpose: The purpose of the paper is to complement existing discussions within the scientific area concerning the effects mandatory audit-firm rotation have on audit quality. The purpose is met while a study on firm-level is conducted combining aspects in fact with aspects in appearance related to a limitation in the length of the firm-client relationship. Method: A multiple logistic regression will be used to analyze data from annual reports and audit opinions against audit quality in fact. A survey has been designed, which intends to study external third parties’ perception of audit quality in appearance. The literature chapter will form the basis for definitions as well as analyzes. Conclusions: Through an analysis of the papers result for both audit quality in fact and audit quality in appearance, a comprehensive conclusion of total audit quality can be made. In regard to audit quality in fact, our result show no significant effect between the length of the firm-client relationship and audit quality. Hence, neither the auditor’s independence nor competence are assumed to be substantially affected by the change in regulation. However, an indirect impact on the auditor’s inde

(2)-Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5-trisubstituted (2)-thiazolines. These (2)-thiazolines were synthesized from readily accessible/commercially available ,-unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an ON acyl migration reaction as key steps. The final products were obtained in good yields with up to 97% enantiomeric excess.

Thiazolino fused 2-pyridones peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibres. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications.

Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.

Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human α-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates α-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled α-synuclein show that upon FN075 addition, α-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain β-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for α-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry.

Meeting abstract

Ringfused bicyclic 2-pyridones exhibit interesting biological properties against pili assembly in uropathogenic E. coli1 as well as curli formation2. In the strive for new ring-fused central fragments highly selective synthetic routes to the 2-furanone or 2-pyrone containing tricyclic scaffolds 1 and 2 have been developed.

A fluorine-labeled selenide linker for installing terminal isolated olefins has been synthesized in high overall yield. The resin-bound linker could be glycosylated both with glycosyl trichloroacetimidates and glycosyl fluorides. The linker did not decompose after oxidation with tBuOOH but underwent beta-elimination when it was subjected to heat. This allowed the released n-pentenyl glycoside 15 to be isolated in excellent yield and purity after filtration.

Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.