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Vibrational optical activity spectral response to the conformational behaviour of antibiotic glycopeptides

Boek - Dissertatie

Fundamental spectroscopic research revolves around comprehending the subject technique on a theoretical level and discovering in what chemical queries it is deployable. This dissertation attempts to do this for the technique called Raman optical activity (ROA). ROA is the detection of a differential Raman intensity between sending in right- and left circular polarized light or the differential detection of right- or left circular polarized Raman scattered intensities. The preference for one of the circular polarization states finds its origin in the chirality of a system. The main application of ROA were found to be absolute configuration determination of small organic compounds and the secondary structure elucidation of proteins. Only from the unlocking of ROA spectral calculations onwards more sophisticated elucidations took place. Various polypeptides and (poly)carbohydrates became subjects of investigation by combining empirical work with spectral simulations. By 2018, when this thesis was initiated, ROA calculations and analyses were possible for quite sophisticated systems, finally permitting the investigation of molecules that are actually being used in pharmacy, an application area where ROA was believed to be a valuable future contributor. The question that remained, however, was: how exactly can ROA contribute and how should this be done? The main goal of this dissertation is to respond hereon, as such bringing together ROA and pharmacy. The antibiotic glycopeptide molecular class was carefully selected as subject of investigation, the aim being the determination of the conformational ensemble of this molecular class by means of ROA. Besides ROA, also the closely related vibrational circular dichroism (VCD) technique is added to the study. Subsequently, derivatives of vancomycin -oritavancin, dalbavancin, teicoplanin- were recorded, so as to experimentally observe the spectral effect of changing the chemical structure and/or conformation of the glycopeptide. Finally, the vancomycin binding to its biological target, Lipid II -a bacterial cell-wall precursor- was investigated using ROA. The principal conclusion that can be derived from all the above studies is that the aromatic systems that adopt a fixed conformation define the spectral responses, whereas the carbohydrates barely contribute. All combined, the obtained results provide important insights in the applicability of the VOA techniques in the conformational elucidation of challenging, real-world molecular systems. Both the strategies and the type of measurements contained herein represent a step in connecting the ROA field and pharmaceutical world.
Aantal pagina's: 209
Jaar van publicatie:2022
Trefwoorden:Doctoral thesis
Toegankelijkheid:Open