Investigations of DNA and anthracene as agents for drug release

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Farrow, Charlotte M. A. (2022). Investigations of DNA and anthracene as agents for drug release. University of Birmingham. Ph.D.

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Abstract

Targeted drug release has been a strong focus in the pharmaceutical industry in recent
decades in an attempt to minimise the often severe side effects observed in therapeutics.
Many methods of targeted drug release look at incorporating the drug moiety into
nanoparticles, but other techniques can involve an organic drug donor with an attached
targeting vector. Aptamers, single stranded oligonucleotides which can fold into complex
structures capable of binding to non-DNA analytes with high selectivity and specificity, have
often been highlighted as possible vectors for drug delivery. This thesis aims to contribute to
the field of therapeutic delivery by investigations into both organic drug donor molecules and
aptamer-derived directing capabilities.
The first approach of this project primarily involved the synthesis, characterisation, and study
of a range of anthracene-derived nitroxyl (HNO) donors for potential therapeutics. A number
of 9- and 9,10-substituted anthracene diols were designed as dienes for a Diels-Alder
cycloaddition to create an HNO donating molecule capable of photo-initiated release. Further
investigations into the stability of cycloadducts formed, and the conjugation of such moieties
to a range of targeting vectors were attempted. Following this HNO donating theme, an
anthracene-derived Piloty’s acid analogue was also prepared and its behaviour under photoirradiation
investigated.
In a different approach, aptamers for controlled drug capture and release were designed and
investigated for reversible drug binding. By designing short segments of complementary DNA
that would disrupt the secondary structure of the aptamer species, reversible binding could
be demonstrated.
Finally, the challenge of the Covid-19 pandemic led to the use of anthracene-modified
oligonucleotides in the diagnosis of variant species of the virus. Anthracene tags were
designed and synthesised, incorporated into short oligonucleotide probe strands and the
fluorescence changes of the anthracene upon interaction with single base mutations of the
Covid-19 spike protein genome were investigated.