BORIS Theses

BORIS Theses
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Aspects of cyclodextrin host-guest complexes in mass spectrometry

Bruni, Pia Simona (2022). Aspects of cyclodextrin host-guest complexes in mass spectrometry. (Thesis). Universität Bern, Bern

22bruni_ps.pdf - Thesis
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Cancer is a widely spread disease leading to uncontrolled cellular replication that caused 9.6 million deaths worldwide in 2018. One approach in cancer treatment is inhibiting the replication process by the administration of organometallic compounds that bind to DNA. Cisplatin is one of the most prominent organometallic compounds that reached clinical approval. However, it suffers from severe side effects (e.g., nephrotoxicity) and causes the development of resistance. Various other metallorganic drugs have been evaluated for their potential in cancer treatment. Thereof, titanocene dichloride had entered clinical trials, but showed only low patient effcacy. Titanocene dichloride is a representative of the class of the bent metallocene dihalides that comprise a tetrahedral structure with two cyclopentadienyl and two halogenide ligands and a metal ion as central atom. Hydrolysis of the halogenide ligands is a crucial step in the activation of the metallocene, allowing for the interaction with its biological target. Unfortunately, extensive hydrolysis of the halogenide and the cyclopentadienyl ligands is detected for titanocene in aqueous environment at physiological conditions, leading to its inactivation. One approach for increasing the hydrolytic stability of titanocene is its inclusion within the cavity of a macrocyclic host structure. Cyclodextrins are such macrocyclic compounds composed of six to eight 1,4-linked α-D-glucopyranose units that are considered nontoxic upon oral administration. Therefore, several aspects of cyclodextrin host-guest complexes in mass spectrometry have been investigated and are discussed in this thesis. In the first section, the mass spectrometric behavior of cyclodextrins is discussed. The central part of this project was the elucidation of the fragmentation mechanism underlying the decomposition of protonated cyclodextrins. Linearization of the macrocyclic structure upon charge-induced cleavage of a glycosidic bond has been revealed as the initial dissociation step. Further decomposition of the linearized structure is characterized by neutral loss of glucose subunits. This dissociation step has been stated to occur upon charge-remote cleavage of other glycosidic bonds, leading to the elimination of a zwitterionic moiety which is potentially internally rearranged. In the second section, the focus is laid on the interaction between titanocene and cyclodextrins elucidated from mass spectrometric experiments. The obtained data indicated the formation of covalent bonds between titanium and the hydroxy groups at the rim of cyclodextrins rather than the formation of an inclusion complex. Consequently, improvement of the hydrolytic stability of titanocene at physiological pH was not obtained by the interaction of titanocene with cyclodextrins. In-source fragmentation has been found to contribute considerably to the ions detected in full scan mass spectrometry. Therefore, the effect of instrumental parameters on the quality of the obtained full scan mass spectra has been evaluated. While the capillary voltage showed only minor effects, proper adjustment of the capillary temperature and the tube lens voltage signifcantly improved the quality of the obtained data. In conclusion, diverse aspects of cyclodextrin host-guest complexes have been successfully investigated using mass spectrometry showing the potential of this analytical technique for various applications.

Item Type: Thesis
Dissertation Type: Cumulative
Date of Defense: 29 April 2022
Subjects: 500 Science
500 Science > 540 Chemistry
Institute / Center: 08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
Depositing User: Hammer Igor
Date Deposited: 08 Jul 2022 12:19
Last Modified: 08 Jul 2022 12:21

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