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dc.contributor.advisorSmith, Dennis A.
dc.contributor.advisorFarràs, Pau
dc.contributor.advisorAldabbagh, Fawaz
dc.contributor.authorKielty, Patrick
dc.description.abstractNitric oxide (NO) is a gaseous free radical with medicinally significant properties. The NO-releasing prodrug, isosorbide-5-mononitrate (Is5N), is long established for the treatment of angina pectoris. Nitroxides are organic derivatives of NO, and their release from organic carriers (alkoxyamines) reveals useful, reactive alkyl radicals. Heterocycles are rich in chemical and biochemical properties that allow a variety of stimuli, including visible-light, to induce NO or nitroxide release. The bicyclic fused heterocycle isosorbide (1,4:3,6-dianhydro-D-glucitol) is an appropriate substrate for the attachment of NO donor motifs. The broader structural family of isosorbide, the 5-5 ring-fused heterocyclic systems, containing one heteroatom in each ring is reviewed. Conjugated and non-conjugated heterocyclic systems are considered in terms of their reactivity and aromaticity, with the most common ring system being pyrrolo[2,3-b]indole, an important structural motif of natural products. Herein, isosorbide was functionalized with furoxan (1,2,5-oxadiazole 2-oxide) for the first time to give thermally stable adducts that release NO up to 7.5 times faster than Is5N. Protection of isosorbide using MeMgCl-mediated acetylation allowed selective alkylation with furoxan bromides. By increasing the amount of MeMgCl, selectivity of acetylation was switched from isosorbide-5-acetate to isosorbide-2-acetate. Reactivity was rationalized in terms of a more stable 5-alkoxide magnesium salt using DFT, and was further validated by the selective deacetylation of isosorbide-2,5-diacetate. In nature, the unmasking of heterocyclic quinones to form stabilized quinone methide radicals is achieved using bioreduction. Herein, alternative room-temperature visible-light activation is provided using alkoxyamines and bis-alkoxyamines. The nitroxide stable free radical, TEMPO, is released at the same rate and sequentially from both moieties of the bis-alkoxyamine. Selective synthetic modification allowed chromophore deactivation to provide one labile alkoxyamine moiety.en_IE
dc.publisherNUI Galway
dc.subjectprotecting group strategyen_IE
dc.subjectfused heterocyclesen_IE
dc.subjectalkoxyamine homolysisen_IE
dc.subjectvisible-light photolysisen_IE
dc.subjectreaction kineticsen_IE
dc.subjectquinone methideen_IE
dc.subjectheterocyclic quinoneen_IE
dc.subjectlight activationen_IE
dc.subjectOrganic chemistryen_IE
dc.titleHeterocyclic chemistry: Controlled unmasking of nitric oxide and nitroxidesen_IE
dc.contributor.funderIrish Research Councilen_IE
dc.local.noteIn this thesis, new alternatives to the established nitric oxide-releasing anti-angina drug, isosorbide-5-mononitrate (Is5N), are presented. The isosorbide-furoxan-based derivatives release nitric oxide at a faster rate, and are more thermally stable than the clinically used Is5N. Selective synthetic manipulation of renewably-sourced isosorbide is traditionally challenging, but has been achieved via a new, elegant and efficient method using a simple magnesium-based agent. The active forms of anti-cancer quinone drugs are revealed in the body using an intrinsic facet of cellular function, bioreduction. Activation of drugs using visible light has several advantages over traditional methods of administration, including improved targeting of cancerous tissue. Herein, an alternative unmasking of quinones is presented using visible light at room-temperature. The new approach is achieved via release of stable nitroxides, structural analogues of nitric oxide.en_IE

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