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.

No description available.

The collagen telopeptides play an important role for lysyl oxidase-mediated crosslinking, a process which is deregulated during tumour progression. The DEKS motif which is located within the N-terminal telopeptide of the α1 chain of type I collagen has been suggested to adopt a βI-turn conformation upon docking to its triple-helical receptor domain, which seems to be critical for lysyl oxidase-catalysed deamination and subsequent crosslinking by Schiff-base formation. Herein, the design and synthesis of cyclic peptides which constrain the DEKS sequence in a β-turn conformation will be described. Lysine-side chain attachment to 2-chlorotrityl chloride-modified polystyrene resin followed by microwave-assisted solid-phase peptide synthesis and on-resin cyclisation allowed for an efficient access to head-to-tail cyclised DEKS-derived cyclic penta- and hexapeptides. An Nε-(4-fluorobenzoyl)lysine residue was included in the cyclopeptides to allow their potential radiolabelling with fluorine-18 for PET imaging of lysyl oxidase. Conformational analysis by ¹H NMR and chiroptical (electronic and vibrational CD) spectroscopy together with MD simulations demonstrated that the concomitant incorporation of a D-proline and an additional lysine for potential radiolabel attachment accounts for a reliable induction of the desired βI-turn structure in the DEKS motif in both DMSO and water as solvents. The stabilised conformation of the cyclohexapeptide is further reflected by its resistance to trypsin-mediated degradation. In addition, the deaminated analogue containing allysine in place of lysine has been synthesised via the corresponding ε-hydroxynorleucine containing cyclohexapeptide. Both ε-hydroxynorleucine and allysine containing cyclic hexapeptides have been subjected to conformational analysis in the same manner as the lysine-based parent structure. Thus, both a conformationally restricted lysyl oxidase substrate and product have been synthetically accessed, which will enable their potential use for molecular imaging of these important enzymes.

Funktionalisierte organische Perylenbisimidfarbstoffe (PBI) und aus Cadmiumselenid bestehende Halbleiternanokristalle werden hinsichtlich physikalischer sowie chemischer Wechselwirkungsprozesse miteinander und mit ihrer Umgebung mittels zeitaufgelöster optischer Spektroskopie untersucht. Im Mittelpunkt der Studien an diesem organisch/anorganischen Modellsystem nanoskopischer Größe steht die Aggregatbildungskinetik und die Identifikation und Quantifizierung von Transferpozessen. Die Anbindung der gut löslichen PBI-Farbstoffe an die Oberfläche solcher Halbleiternanokristalle mittels spezieller Ankergruppen wird durch Selbstorganisation in Lösung realisiert. Die Kombination von Absorptions- und zeitaufgelöster Fluoreszenzspektroskopie zeigt einen unterschiedlich starken Einfluss von Liganden und Farbstoffen auf die Fluoreszenzlöschung der Nanokristalle und belegt, dass Resonanzenergietransfer zum Farbstoff nur in sehr geringem Maße die physikalische Ursache der Fluoreszenzlöschung ist. Die Anzahl adsorbierter Farbstoffe und die Stärke der Fluoreszenzlöschung eines einzelnen Farbstoffmoleküls werden aus zeitaufgelösten Einzelmolekülexperimenten an immobilisierten Emittern gewonnen, welche den direkten spektroskopischen Zugang zur Verteilung gebundener und freier Farbstoffe/Nanokristalle erlaubt. Darüber hinaus werden ankergruppen- und umgebungsspezifische Einflüsse auf die Konformations- und Orientierungsdynamik von Perylenbisimidmolekülen dargestellt. Abschließend werden photo-physikalische Gemeinsamkeiten chemisch unterschiedlich hervorgerufener Fluoreszenzlöschungsprozesse herausgearbeitet und im Kontext von Einzelkristall-Blinkprozessen diskutiert.

Drei ausgewählt makromolekulare Systeme: DNA, amphiphile Block-Bürstenpolymere, und amphiphile, hyperverzweigte Polyglycerine wurden untersucht, um die Zusammenhang zwischen Struktur, Eigenschaften, und potentiellen Anwendung auf der Ebene einzelner Moleküle zu widmen. Unterschiedliche DNA Konformationen: (i) supercoiled DNA, (ii) gestreckte doppelsträngige DNA, die teilweise in zwei Einzelstränge aufgeschmolzen ist, (iii) DNA mit einem überdehnten Rückgrat, (iv) entspannter, ungedehnter Ring und (v) kompaktes Knäuel wurden untersucht, um direkt DNA Konformationen mit mechanischen Eigenschaften, wie der Kopplung von Streckung und Verdrillung zu korrelieren. Mit Hilfe eines Kraftmikroskops, mit dem man eine Kraft parallel zur Oberfläche anlegen kann, wurden die plasmidischen DNA Moleküle auf bis zum 2.1-fachen der ursprünglichen B-Form Länge gestreckt und dann gerissen. Die Strukturen einzelner Amphiphilen Block-Bürstenpolymere auf unterschiedlichen Oberflächen wurden investigiert. Aus Chloroform-Lösung auf Glimmer abgeschiedene Polymere wiesen wurmartige Konformationen auf. Wegen der unterschiedlichen Oberflächenaffinitäten der Seitenketten sind diese zu einem Teil kollabiert, während sich ein anderer Teil ausstreckt. Das an Kaulquappen erinnernde Ergebnis ist eine Struktur mit rückgefalteten Kettenteilen. Aus wässriger Lösung abgeschieden bilden diese amphiphilen Block-Bürstenpolymere supramolekulare Aggregate auf der Oberfläche. Die amphiphile Kern-Schale-Strukturen der hyperverzweigten Polyglycerinen und ihre Verkapselungs- und Transportkapazität für typische Gastmoleküle wie Nil Rot und Pyren wurden mit Hilfe von SFM, Lichtstreu-, und Spektroskopie-Methoden examiniert. Die Ergebnisse zeigen, dass die Polymere verschiedene Gastmoleküle sowohl in unimolekulan Mizellen wie auch in polymeren Mizellen verkapseln und transportieren. Das Polymer ist ein vielversprechender Kandidat für die gleichzeitige Bereitstellung von zwei hydrophoben Pharmaka. / Three macromolecular systems: DNA, amphiphilic cylindrical polymer brushes, and amphiphilic core-shell structured hyperbranched polyglycerol (hPG) were investigated in order to investigate correlations between structure, properties and potential applications at the single molecule level. Different single DNA conformations: (i) supercoiled DNA, (ii) stretched DNA, partially melted into two single strands, (iii) DNA with an overstretched backbone, (iv) relaxed circles without stretching, and (v) compact coils were studied on the surface to directly correlate DNA conformations to mechanical properties such as twist-stretch coupling. The plasmid DNA molecules were stretched further, up to 2.1 times their original length and ruptured with a Scanning Force Microscope (SFM), exerting a force parallel to the surface. The structures of single cylindrical polymer brushes adsorbed on different surfaces were explored. The brush polymers reveal worm-like chain conformations on mica, after being deposited from a chloroform solution. Due to different affinities of the side chains to the surface, parts of the side chains collapsed, while others fully extended on the surface, resulting in a “tadpole like” or a back-folding structure. Deposited from an aqueous solution, the dual cylindrical polymer brushes form supramolecular aggregates on the surface. The supramolecular structure of hyperbranded polyglycerol and its encapsulation and transportation capacities for typical guest molecules, such as nile red and pyrene were examined by SFM, light scattering and spectroscopy methods. The polymer showed bi-functional carrier properties: it encapsulates and transports guest molecules in both, a “unimolecular micelle” and polymeric micelle type mechanism. The capacity of co-loading of two drugs and controlled release makes it a promising candidate for simultaneous delivery of two hydrophobic drugs in cancer combination therapy.

No description available.

Heterogeneous line broadening and spectral diffusion of the fluorescence emission spectra of perylene diimide molecules have been investigated by means of time dependent single molecule spectroscopy. The influence of temperature and environment has been studied and reveals strong correlation to spectral diffusion processes. We followed the freezing of the molecular mobility of quasi free molecules on the surface upon temperature lowering and by embedding into a poly(methyl methacrylate) (PMMA) polymer. Thereby changes of optical transition energies as a result of both intramolecular changes of conformation and external induced dynamics by the surrounding polymer matrix could be observed. Simulations of spectral fluctuations within a two-level system (TLS) model showed good agreement with the experimental findings.

Organic solar cells (OSCs) based on non-fullerene acceptors (NFAs) have attracted a great deal of attention in recent years due to their rapidly increasing efficiency and enormous potential. In this work, the optical and electronic properties of systems containing the very promising non-fullerene acceptor PYT have been thoroughly studied with the use of the density functional theory (DFT) and the time-dependent density functional theory (TDDFT). By changing the electron linker from thiophene to furan and selenophene, respectively, the PYT was divided into three variants, each of which was studied independently. In addition, these three systems were combined with the donor PBDB-T to generate two distinct interface conformations. The properties studied in this work include the optimized geometries, HOMO-LUMO levels, UV-Vis spectra, frontier molecular orbitals (FMOs), natural transition orbitals (NTOs), density of states (DOS), dipole moments, open-circuit voltages, exciton binding energies, and local exciton (LE) and charge transfer (CT) energies. The calculations were performed in chlorobenzene solution utilizing the polarizable continuum model (PCM). It was discovered that PBDB-T/PY-Se exhibited remarkable flatness employing the π-π stacking conformation which corresponds well with the excellent D/A compatibility observed experimentally. All interfaces displayed appropriate positioning of the HOMO-LUMO levels, with the acceptor dominating the LUMO and the donor dominating the HOMO, with HOMO-LUMO gaps ranging between 1.34 and 1.38 eV. The differences in the interchanging of the electron linker were not that significant, and neither was the change in interface conformation in terms of the HOMO-LUMO levels. This may indicate that the system can be effective even without the presence of a π-π stacking conformation. The first excited states for all interface systems were shown to be pure CT transitions, and on average, 80% of the states exhibit CT character. The remaining contributions consisted of transitions within the pure materials, with a larger contribution within the acceptor. The theoretical results of this study indicate that systems containing the novel polymer acceptor PYT and its variants PY-O and PY-Se exhibit very intriguing properties, and further development of OSCs containing these polymers might further aid in the development of high-performance OSCs. / Organiska solceller (OSC) baserade på icke-fullerenacceptorer (NFA) har väckt stor uppmärksamhet de senaste åren på grund av dess snabbt ökande effektivitet och enorma potential. I detta arbete har de optiska och elektroniska egenskaperna hos system innehållande den mycket lovande icke-fullerenacceptorn PYT studerats grundligt med användning av täthetsfunktionalteorin (DFT) och den tidsberoende täthetsfunktionalteorin (TDDFT). Genom att ändra elektronförbindelsen från tiofen till furan respektive selenofen så delades PYT upp i tre varianter som var och en studerades oberoende av varandra. Dessutom kombinerades dessa tre system med donatorn PBDB-T för att generera två distinkta gränssnittskonformationer. Egenskaperna som studeras i detta arbete inkluderar optimerade geometrier, HOMO-LUMO-nivåer, UV-vis spektra, gränsmolekylära orbitaler (FMO), naturliga övergångsorbitaler (NTO), tillståndstäthet (DOS), dipolmoment, tomgångsspänning, excitonbindningsenergi samt lokal exciton (LE) och laddningsöverförings (CT) energier. Beräkningarna utfördes i klorbensenlösning med användning av den polariserbara kontinuummodellen (PCM). I resultatet uppvisade PBDB-T/PY-Se en anmärkningsvärd planhet med användning av π-π staplingskonformationen som överensstämmer väl med den utmärkta D/A-kompatibiliteten som observerats experimentellt. Alla gränssnitt visade lämplig positionering av HOMO-LUMO-nivåerna, med acceptorn som dominerade LUMO och donatorn som dominerade HOMO, med HOMO-LUMO-gap mellan 1.34 och 1.38 eV. Skillnaderna i utbytet av elektronförbindelsen visade sig inte vara signifikanta och inte heller skillnaden i gränssnittskonformation när det gäller HOMO-LUMO-nivåerna. Detta kan indikera att systemet kan vara effektivt även utan förekomst av π-π staplingskonformation. De första exciterade tillstånden för alla gränssnittssystem visade sig vara rena CT-övergångar och i genomsnitt uppvisade 80% av tillstånden CT-karaktär. Resterande andel bestod av övergångar inom de rena materialen med en större andel inom acceptorn. De teoretiska resultaten av denna studie indikerar att system innehållande den nya polymeracceptorn PYT och dess varianter PY-O och PY-Se uppvisar mycket spännande egenskaper samt att vidareutveckling av OSC:er som innehåller dessa polymerer ytterligare kan hjälpa till i utvecklingen av högpresterande OSC:er.