Systematic analysis of the fragmentation of natural products by tandem mass spectrometry and computational method

Abstract

This thesis consists of the studies of three types of natural products - a-amino acids, flavonoids, and polyether ionophores. A natural product is defined as a natural compound or substance produced in nature by living organisms. A better understanding of natural products from an analytical approach is crucial to many scientific disciplines. This research focused on the systematic analysis of the
fragmentation of natural products by mass spectrometry and computational methods in order to develop a robust methodology that can be applied to a broader range of natural products and other research areas.

The first part of this research used tandem mass spectrometry to systematically analyse the fragmentation of all 20 proteinogenic a-amino acids in both positive and negative ionisation modes. The combination of computational modelling with the correlation between side chain functionalities and fragmentation pathways is compared and summarised. Isomers such as leucine and isoleucine are differentiated, and the differences are rationalised using the developed methodology. The second part tested and improved the analytical methodology in the analysis of flavonoids. More than 30 flavonoids from six classes were investigated. Isomeric flavonoids were differentiated. Diagnostic product ions from the positive ion mode collision induced dissociation spectra were
identified.

Polyether ionophore antibiotics were selected as the final part of the research due to their structural complexity, importance in pharmaceutical development, and tendencies to isomerise in solution. The unique properties of the polyethers provide an optimal ground to test the robustness of the methodology developed in the studies of the smaller molecules. By combining high-resolution ion
mobility mass spectrometry data, tandem mass spectrometry, and computational methods, differentiation of isomers of salinomycin and narasin was achieved. The addition of the study of metal cation complexation provided novel fragmentation pathways, which led to a better understanding of the structural elucidation of the selected polyethers. Complete assignment of the product ions was also achieved for salinomycin monosodium cation and its isomer equivalent. Additional computational data offered a degree of improved rationalisation to the experimental observations.

Results generated from this research demonstrated the powerful approach of combining mass spectrometry with computational methods for the analysis of natural products. It provides an excellent foundation for more challenging future work in related research fields.

Date of Award	3 Oct 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Chris Arthur (Supervisor) & Paul J Gates (Supervisor)