35 KJEMI 4 2025 Universitet og dato: UiT, Kjemisk institutt, 26. august, 2025 Navn: Eskil Andre Karlsen Veiledere: Hovedveileder: Professor John Sigurd Mjøen Svendsen, institutt for kjemi UiT / Amicoat AS, Co-veiledere: Professor Tore Lejon, institutt for kjemi UiT og Postdoktor Marianne Hagensen Paulsen, institutt for kjemi UiT Opponenter: First opponent: Professor Magne O. Sydnes, UiB Second opponent: Professor Claus E. Moser, Universitet i København Committee coordinator: Forsker Manuel K. Langer, IK, UiT Tittel på prøveforelesning: Antimicrobial peptides – Design, development and application Tittel på avhandling: Towards general and effective antifouling surfaces – covalent surface attachment of antimicrobial peptides Sammendrag: Healthcare-associated infections are of grave concern in healthcare facilities as these acquired infections pose a significant threat to the quality of life across the globe. Healthcare-associated infections are often related to the use of medical devices like catheters, joint prostheses, and implants. Medical devices are especially prone to bacterial growth, which can result in possible life-threatening complications. With the continued rise of antibiotic resistance, it is of utmost importance to minimize the numbers of medical device-associated infections induced by multidrug-resistant bacteria. Currently, there are prophylactic options in place to prevent biofilm-related infections, such as coating the medical devices with antibiotics or antiseptics. However, there are limitations to both antibiotics and antiseptics. These are not permanently incorporated into the medical device, causing the active ingredient to leak into the surrounding tissues and potentially increases the risk for acute hypersensitivity reactions and cytotoxicity, exacerbating the antibiotic-resistant problem and harming the environment with pollution. A promising class of antimicrobials that has the potential to evade the current problems are cationic antimicrobial peptides (AMPs), which can be permanently incorporated into medical devices. Due to their distinct characteristics, cationic AMPs can contribute to lessen the overall number of infection cases related to medical devices and reduce the need for potential treatment. The presented project aimed to create a cationic AMP-coated surface material. The synthesized peptides were structurally distinctive with all peptide analogues having an azido group incorporated, which were to be covalently incorporated to alkyne-modified surfaces using the copper(I)-catalyzed azide-alkyne cycloaddition and had their ability to inhibit bacterial surface growth accessed. The peptides followed an RW-sequence with the intention of investigation the effects of lipophilicity modulation, PEGylation, cyclization, and surface density have against Staphylococcus epidermidis colonization on a pre-diced gold surface and a modified glass surface with gold nanoparticles. The bacterial response of Escherichia coli was also studied by subjecting the bacterium to a cationic AMP-coated glass surface. acceptors. Mechanistic investigations revealed that the intramolecular photoredox catalyzed radical group transfer of the vinyl or alkynyl group from silicon to carbon proceeds through a pathway involving both single electron transfer (SET), halogen atom transfer (XAT) and chain propagation, which also includes radical cyclization and spontaneous ring fragmentation of the resulting cyclic intermediate. The protocol was successfully applied to a wide range of substrates and afforded the desired products in moderate to excellent yields with high diastereoselectivities. Second, we investigated the photoredox catalyzed intermolecular radical addition of electron-deficient radicals onto divinyltetramethyldisiloxane. To our surprise, the anticipated radical cyclization did not take place, but a product resulting from an atom transfer radical addition (ATRA) process was formed instead. Thus, we turned our attention to the optimization of the intermolecular ATRA reaction. While this work requires further investigation, it orientated us towards our third objective. Finally, we developed a preliminary protocol for the photocatalyst-free visible light-mediated intermolecular ATRA reaction between α-iodoketones and trimethylvinylsilane. The protocol was successfully applied to a selection of substrates. However, a high variability of isolated yields was observed despite extensive screening of the reaction conditions, which suggests that the optimal conditions may be substrate dependent. We postulated that the desired ATRA reaction was initiated by photoexcitation of a halogen bond (XB) complex and operated through chain propagation. Overall, we have successfully developed both inter- and intramolecular radical addition processes of alkyl radicals to vinylsilanes. Through our work, we have exploited multiple ways to generate alkyl radicals from alkyl halide precursors using visible light-mediated techniques and have gained insight onto the different mechanisms of these reactions. We anticipate that these results will establish alkenyl and alkynyl silanes as radical acceptors in contemporary radical chemistry.
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