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- Peintner, Stefan, 1991-
(author)
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Shape Matters : Characterization of Weak Interactions and Macrocycles by Conformational Analysis
- 2022
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Doctoral thesis (other academic/artistic)abstract
- When studying conformational ensembles, it is most challenging to identify and characterize rapidly interconverting individual conformers. A precise description of the structural dynamics, however, rewards viable knowledge on conformation stabilizing forces as well as on the impact of external influences on the conformer composition. This thesis focusses on the solution NMR spectroscopic conformational analysis of flexible molecules with the aim to unveil the impact, strength and geometry of a single weak non-covalent interaction, a halogen bond. In addition, I investigated the impact of the solvent polarity on the conformational distribution of macrocyclic drugs.Weak interactions are difficult to characterize in solution with current techniques. Therefore, I designed a peptidic β-hairpin model system that serves as platform to probe a single weak halogen bond in solution. The presented strategy benefits from the cooperativity of non-covalent forces, from preorganization, and from the entropic advantage of studying an interaction in an intramolecular setting. A weak C−I···O halogen bond was characterized thermodynamically and geometrically using NMR-based variable temperature, NOE, scalar coupling and RDC analyses. Time-averaged NMR parameters were deconvoluted with NAMFIS and by Singular Value Decomposition as implemented into MSpin. Characterization of such a weak interaction (ΔΔG° < 0.9 kJ/mol) in dilute solution is remarkable.Making use of NMR-based ensemble analysis, I further studied the impact of solvent polarity on the conformational distribution of macrocyclic drugs that do not obey Lipinski’s Rule-of-5, yet experience good membrane permeability. I demonstrate experimentally that this class of compounds behaves as molecular chameleons by adjusting their conformation to shield or expose polar functionalities as an adaptation to the surrounding environment. Solution ensembles in D2O and CDCl3 mimicking the plasma/cytosol and cell membrane, respectively, were determined and thus revealed that the flexibility of studied macrocycles facilitates a major difference in size and polarity between different environments. Overall, this thesis demonstrates the capabilities and precision of solution NMR spectroscopic conformation analysis techniques, and two possible applications of their use for solving scientific challenges of high relevance to medicinal and organic chemistry.
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- Umereweneza, Daniel
(author)
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Discovery of Secondary Metabolites from Rwandese Medicinal Plants : Isolation, Characterization and Biological Activity
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Plants have served as the principal source of medicines in different parts of the world through the ages. Herb-derived medicines have been used as decoctions, infusions, tinctures or single substance drugs. Due to their impressive possibility of diversification, plants have also provided an immense universe of creativity for synthetic chemists, who constantly make useful new molecules inspired by the natural molecular architecture.The goal of this thesis work was to investigate secondary metabolites isolated from selected Rwandese medicinal plants. It focused specifically on the isolation, the characterization and the determination of the biological activity of natural products. The investigated plants belong to the families of Myrtaceae (Eucalyptus melliodora and Eucalyptus anceps), Fabaceae (Eriosema montanum), Lamiaceae (Clerodendrum myricoides) and Asteraceae (Senecio mannii). These were selected from the Rwandese flora based on information collected from traditional healers, and from the literature. The study made use of chromatographic, spectroscopic and spectrometric methods for separation, purification and structure elucidation of the plant constituents.In paper I, the chemical composition and antifungal activity of essential oils of E. melliodora and E. anceps were discussed. The essential oils were composed of mono- and diterpenes, and their alcohol derivatives. The essential oil mixtures exhibited antifungal activity against food spoilage fungi.In paper II, E. montanum was investigated and a total of 20 compounds were isolated including two new prenylated dihydrochalcones and eighteen known secondary metabolites. Their antibacterial activities and cytotoxicity were determined. In paper III, the isolation of three new and two known iridoid glycosides from C. myricoides was reported along with the antiviral activities of the crude extract and of the isolates. In paper IV, the phytochemical investigation of S. mannii was reported. It afforded one new silphiperfolanol angelate ester, two new macrocyclic pyrrolizidine alkaloids, and five known secondary metabolites. Two new synthetic derivatives were obtained by structural modification of 2-angeloyloxy-5,8-dihydroxypresilphiperfolane. The relative stereochemistry of senaetnine was investigated by NAMFIS and confirmed to be 7R, 12R, and 13R.The new compounds isolated in this study have shown biological activities, and may provide lead compounds for drug discovery and technological applications.
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- Wilcox, Scott, 1993-
(author)
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Characterising Weak Interactions in Solution. : An NMR Spectroscopic Approach.
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Detecting and characterising weak interactions in dilute solutions is challenging. This thesis focusses on the development of a new NMR spectroscopic strategy to do so, whilst also investigates a newly proposed type of weak interaction in solution with currently available NMR techniques.Newly developed lanthanide(III) ion complexes bearing Lewis basic and Lewis acidic functionalities were synthesised, and their paramagnetic properties were successfully exploited. In both instances and in an iterative manner, a series of small molecules of different hydrogen- and halogen-bond strengths were titrated against a paramagnetic Lewis base/acid host in the polar aprotic solvent d-MeCN. In all cases, binding phenomena were detected at 1.82-2.20 mM concentrations of host – around an order of magnitude lower than previously attainable. Titrations against diamagnetic references, with Lu(III) complexes and with untagged Lewis bases, provided small, almost undetectable changes in chemical shift upon binding. Dilutions and titration against non-bonding paramagnetic complexes, as well as with a non-bonding species, proved that the paramagnetic properties were indeed transferred through binding the Lewis base or acid to the respective titrants. Association constants were determined for each binding pair, as well as their relative geometry to one another, providing evidence of these weak interactions over a much lower concentration range than was previously possible. This strategy represents the first use of paramagnetic NMR to study weak, small-molecule interactions in solution, thus opening up a whole new field of research with potential applications as a new method in the supramolecular toolbox.In this thesis I also disprove the existence of the recently proposed ‘nucleophilic iodonium interaction,’ a hypothetical force between cationic silver(I) and cationic iodine(I) complexes in solution. Through means of 1H,15N HMBC and DOSY NMR experiments, the lack of interaction between iodine(I) and silver(I) in mixtures of both fast-exchanging bis(pyridine) complexes and slow-exchanging 1,2-bis((pyridine-2-ylethynyl)-benzene) complexes of the two is demonstrated. Testing purposefully contaminated samples of each, separately and in a mixture, lead to the conclusion that the initially published results were anomalous due to wet, consequently decomposed samples. DFT calculations corroborate the experimental findings, suggesting a π-π interactions to be responsible for previously reported crystal structure. These results highlight the need for the careful appraisal of new scientific ideas and the critical interpretation of experimental and computational data.
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