Heterocyclic chemistry: Controlled unmasking of nitric oxide and nitroxides

Nitric 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.

Funder

Irish Research Council

Publisher

NUI Galway

Rights

Attribution-NonCommercial-NoDerivs 3.0 Ireland

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Collections

University of Galway Theses (PhD Theses)