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Deciphering the Biochemistry of Acetaldehyde using Small Molecule Tools: From Hangovers to Cancer

thesis
posted on 2025-02-04, 12:20 authored by Liam A. Thomas

Acetaldehyde (AcH) is a highly reactive and volatile electrophile with wide ranging effects on biology. AcH is formed as the first metabolite of ethanol and is proposed to be the cause of alcohol-induced genotoxicity. AcH has further been implicated in an array of physiological responses to alcohol consumption, including memory loss, loss of motor control, and ‘hangovers’. Studying AcH in biologically relevant conditions has proven difficult due to its rapid reactivity and high volatility. To assist in studying AcH-relevant biochemistry, chemical tools are required. This work outlines the development of phthalimide- and benzotriazole-based AcH-(and other aldehyde) releasing prodrugs to enable accurate dosing of AcH in cells. The release kinetics and stability of the tools were characterised by NMR before their toxicity was profiled within a model liver cancer cell line (HepG2). The tool compounds exhibit comparable toxicity (or in some cases greater toxicity) than the respective aldehyde. Alongside AcH releasers, classical chemistry methods are explored for scavenging and quantifying AcH. Techniques such as the Friedlander annulation and 3-aza-Cope rearrangement are investigated, and their limitations are outlined. The fundamental reactivity and biochemistry of AcH and biomolecules is also explored. Proline amide (and other amino acid amides) act as aldol catalysts, leading to the production of the AcH self-aldol product crotonaldehyde. Histone H2A/H2B dimer, previously thought to be non-catalytic, is also shown to enhance self-aldol condensation reactions. Tetrahydrofolate, a natural scavenger of formaldehyde, is also shown to react with AcH and propionaldehyde. Overall, this work has developed a new chemical toolkit to study AcH biology and provides insight into the fundamental chemistry undertaken by AcH under physiologically relevant conditions.

History

Supervisor(s)

Richard Hopkinson

Date of award

2025-01-16

Author affiliation

School of Chemistry

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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