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The Design and Synthesis of Two-Photon Excitable Fluorescent Histone Deacetylase Inhibitors

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Dissertation embargoed until 24th April 2026(1.17 MB)

Date

2022

Authors

Williamson, Jade

Supervisor

Fleming, Cassandra

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Degree name

Bachelor of Advanced Science (Honours)

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Publisher

Auckland University of Technology

Abstract

This project focuses on the development of HDAC inhibitors that possess innate fluorescent properties. More specifically a potential fluorescent 6-amino-2,3-naphthalimide derived HDAC inhibitor has been synthesised, as a potential tool for cellular imaging studies. The abnormal regulation of HDAC activity has been linked to a number of diseases such as Alzheimer's, Parkinson’s, cancer, and many more. HDAC inhibitors are able to restore the regulation of these enzymes to help treat these problems. The synthesis of the target molecule included four main reactions; a nucleophilic acyl substitution to install the imide, followed by an amination at the 6-position of the naphthalimide ring, then hydrolysis of the tert-butyl ester, and finally an amide coupling to install the zinc binding group. NMR spectroscopy and mass spectrometry analysis supported that the target molecule has successfully been synthesised. Upon optimisation of the methodology needed to access such compounds, we attempted to synthesise three derivatives of the target compound by changing the amino group at the 6-position. The target compound 43 and the derivative compound 64 were also analysed for their HDAC activity, compound 43 showed incredibly good selectivity for class I HDACs 1 and 3, and compound 64 wasn’t as strong but still quite good results in terms of selectivity.

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https://hdl.handle.net/10292/16100

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Bachelor with Honours Dissertations - open access