New imidazotetrazinones have been synthesised that possess features in their structures
to release aziridinium ions upon ring opening. Unstable 2-aminoethylisocyanates were
required in this preparation, which were synthesized with BOC-protection of the amino
group to counteract the reactivity of the amine towards the isocyanate group in the case
of aliphatic amines; in contrast, anilinoethylisocyanates were synthesized unprotected.
Substituents with a range of electron-withdrawing and electron-releasing properties
were introduced at the p-position of the aniline ring. A 13C-labelled study confirmed the
release of the aziridinium ion by these imidazotetrazinones in neutral pH buffer
solution. Furthermore the kinetics of the hydrolysis in neutral aqueous solution of some
these new tetrazines were similar to temozolomide, in addition to useful acid stability.
Other imidazotetrazinones were synthesised for the purpose of releasing alcohols and
phenols. Their synthesis was performed with a one-carbon linker between the
imidazotetrazinone 3-position and the alcohols or phenols to be released. The release
of alcohol and phenol through the hydrolysis of the intermediate diazonium ions to the
unstable hemiacetals that decomposed to the alcohol and phenol was confirmed by 1H
NMR. The kinetics of the hydrolysis of these tetrazines in neutral aqueous solution
showed a faster reaction rate compared with temozolomide (t1/2 = 0.53 and 0.36 h
compared with temozolomide 1.4 h). / Full text was made available at the end of the embargo period, 1st Feb 2016.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/4418 |
| Date | January 2010 |
| Creators | Garelnabi, Elrashied A.E. |
| Contributors | Wheelhouse, Richard T. |
| Publisher | University of Bradford, Institute of Cancer Therapeutics & School of Pharmacy |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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