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University of Bradford Ethesis New applications of Imidazotetrazinone prodrugs. Synthesis and mechanistic investigation of novel imidazotetrazinones as prodrugs of aziridines and as traceless carriers for drug delivery to the central nervous system. Item Type Thesis Authors Garelnabi, Elrashied A.E. 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>. Download date 30/09/2021 03:47:25 Link to Item http://hdl.handle.net/10454/4418 University of Bradford eThesis This thesis is hosted in Bradford Scholars – The University of Bradford Open Access repository. Visit the repository for full metadata or to contact the repository team © University of Bradford. This work is licenced for reuse under a Creative Commons Licence. New Applications of Imidazotetrazinone Prodrugs Synthesis and mechanistic investigation of novel imidazotetrazinones as prodrugs of aziridines and as traceless carriers for drug delivery to the central nervous system. Elrashied Ali Elobaid GARELNABI Submitted for the degree of Doctor of Philosophy Institute of Cancer Therapeutics & School of Pharmacy BRADFORD UNIVERSITY 2010 Abstract 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). i Table of Contents ABBREVIATIONS .......................................................................................................... iv AKNOWLEDGEMENTS................................................................................................. vii Chapter 1 Introduction ................................................................................................. 1 1.1 Imidazotetrazinone origin as a prodrug delivery system ............................................... 1 1.2 Imidazotetrazinone chemistry ....................................................................................... 3 1.2.1 Imidazotetrazinone aqueous reaction .................................................................................... 3 1.2.2 Reaction with DNA ............................................................................................................... 9 1.2.3. Imidazotetrazinone Synthesis .............................................................................................12 1.3 Imidazotetrazinone Clinical Effect ................................................................................18 1.4 Resistance to Temozolomide treatment .......................................................................22 1.4.1 O6-Methylguanine-DNA methyltransferase MGMT .............................................................22 Inactivation of alkyltransferase ....................................................................................................25 1.4.2 DNA – mismatch repair .......................................................................................................27 1.4.3 Base excision repair and PARP .............................................................................................29 1.5 Design and Rationale ....................................................................................................31 1.5.1 Aziridinium ions of biological interest ..................................................................................31 1.5.2 Design of Aziridinium-ion-release imidazotetrazinones ........................................................34 Chapter 2 Synthesis of Imidazotetrazinones for Aziridine Release ............................. 36 2.1 Introduction .................................................................................................................36 2.2 Synthesis ......................................................................................................................36 2.2.1 Synthesis of the Isocyanates ...............................................................................................39 Routes to Isocyanates ..................................................................................................................39 2.2.2 Synthesis of imidazotetrazinones for aziridinium ion release .............................................46 2.2.2.1 Imidazotetrazinones bearing aliphatic amines: ...............................................................46 Synthesis of the 3-(2-aminoethyl)-imidazotetrazinone HBr salt 54 ................................................46 Synthesis of the aliphatic amine-linked-bisimidazotetrazinone 55 ................................................52 Synthesis of 3-(N-Benzylaminoethyl)imidazotetrazinone HBr salt 56 ............................................56 2.2.2.2 Imidazotetrazinones bearing anilines ..............................................................................59 Imidazotetrazinones synthesized from p-substituted anilines .......................................................59 Synthesis of bisimidazotetrazinones 58a, b and c .........................................................................62 Imidazotetrazinones from p-substituted-N-methylaniline.............................................................64 Reflection on the Chemistry of the Anilinoethylimidazotetrazinones .........................................66 Purification Control .....................................................................................................................67 The synthesis of 13C-1'-labelled imidazotetrazinone .....................................................................69 New Imidazotetrazinones Available for Biological Evaluation .....................................................73 Chapter 3 Mechanistic Evaluation of Imidazotetrazinones for Aziridinium Ion Release ................................................................................................................................... 75 3.1 Introduction .................................................................................................................75 3.2 NMR Studies of the ring opening reaction ....................................................................75 3.3 Hydrolysis Kinetics of Aziridinium-ion-release imidazotetrazinones ............................83 3.3.1 Hydrolysis kinetics at pH 4 ...................................................................................................84 3.3.2 Hydrolysis kinetics at pH 7.4 ................................................................................................87 3.3.3 Hydrolysis kinetics at pH 8 ..................................................................................................93 3.4 Conclusions ..................................................................................................................96 NMR study conclusion .................................................................................................................96 ii U.V. kinetics study conclusion ......................................................................................................96 Chapter 4 Imidazotetrazinones for Alcohol or Phenol Release ................................. 100 4.1 Introduction ...............................................................................................................100 4.2 Design .........................................................................................................................100 4.3 Synthesis ....................................................................................................................101 4.3.1 Synthesis of the Isocyanates .............................................................................................. 102 4.3.2 Synthesis of an imidazotetrazinone for the release of furfuryl alcohol................................ 102 4.3.3 Synthesis of an imidazotetrazinone for the release of phenol ............................................ 103 4.4 Mechanistic Evaluation of the Imidazotetrazinones for Alcohol and Phenol release .104 4.4.1 NMR Evaluation of alcohol
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