Theses and Dissertations

ORCID

https://orcid.org/0000-0003-3062-4271

Advisor

Patrick, Amanda L.

Committee Member

Emerson, Joseph P.

Committee Member

Mlsna, Todd E.

Committee Member

Webster, Charles Edwin

Committee Member

Wipf, David O.

Date of Degree

8-13-2024

Original embargo terms

Immediate Worldwide Access

Document Type

Dissertation - Campus Access Only

Major

Chemistry

Degree Name

Doctor of Philosophy (Ph.D.)

College

College of Arts and Sciences

Department

Department of Chemistry

Abstract

Mass spectrometry is a commonly used technique in the modern sports anti-doping laboratory. Characteristic product ions observed in tandem mass spectrometry (MS/MS) can be used to identify prohibited substances. However, with continuous introduction of novel uncharacterized drugs, there is a need to increase the selectivity and coverage identification of mass spectrometry and non-mass spectrometry-based methods. The use of separations methods, (e.g., chromatography) is another means to identify substances using retention times, providing an additional dimension of analysis. Broadly, this work examines mass spectrometry of small molecules, with a focus on pharmaceuticals of sports anti-doping relevance. To gain a deeper understanding of characteristic product ions and their dissociation pathways, multi-stage mass spectrometry (MSn) and energy-resolved collision induced dissociation (E-resolved CID) were used. Using these methods, two classes of pharmaceuticals were studied: beta-2 agonists and beta blockers. Sequential versus competitive pathways were elucidated for four beta-2 agonists: isoetharine, salbutamol, formoterol, and salmeterol. Water loss is a common dissociation mechanism, with multiple water losses observed where structurally possible. A similar methodology was used for further investigation of the dissociation chemistry of five beta blockers (labetalol, bisoprolol, carteolol, acebutolol, and atenolol). Insights into the nature of the neutral losses and structures of product ions characteristic to the class are highlighted. Isomers that share product ions pose a special challenge, where differentiation is not possible using single collision energy CID-MS. Three sets of isomers with similar MS/MS patterns (leucine and tert¬-leucine, quinoline and isoquinoline, and para-, ortho-, and meta-aminobenzoic acid) were analyzed by E-resolved CID to investigate the analytical utility of this approach for isomer differentiation. Unique “fingerprints” were found among each set of isomers and additional analytical considerations were also investigated. Finally, separation of enantiomers is another special challenge, as MS techniques are “chirality blind”. Ion mobility spectrometry (IMS), a gas-phase separation technique, has been reported to show separation of enantiomers with the aid of drift gas modifiers (DGMs). Chiral butanol was used as a DGM to aid the IMS analysis of salbutamol enantiomers. These efforts were ultimately unsuccessful, which is in line with current literature.

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