Synthesis of Bicyclic Sulfones: Inhibitors of Neuraminidase
| dc.contributor.author | Brant, Michael Glenn | |
| dc.contributor.supervisor | Wulff, Jeremy Earle | |
| dc.date.accessioned | 2015-07-16T22:46:49Z | |
| dc.date.available | 2015-07-16T22:46:49Z | |
| dc.date.copyright | 2015 | en_US |
| dc.date.issued | 2015-07-16 | |
| dc.degree.department | Department of Chemistry | |
| dc.degree.level | Doctor of Philosophy Ph.D. | en_US |
| dc.description.abstract | The lithiation of 3-sulfolene followed by subsequent treatment with an alkyl halide electrophile has been previously established as a method to produce 2-substituted-3-sulfolenes. Tandem reactivity with bis-alkyl halides has been observed to afford relatively simple bicyclic products. We hypothesized that it may be possible to access more complex bicyclic systems through use of bis-vinyl ketones as the electrophilic component. Herein, we present the outcome and mechanistic insights for the reaction between a variety of 3-sulfolene and substituted-3-sulfolene anions with bis-vinyl ketones to afford a variety of stereochemically complex fused, bridged and spiro bicyclic archetypes. The potential of these bicyclic-sulfone frameworks to act as molecular scaffolds for the generation of conformationally-restricted enzyme inhibitors is explored. Potent monocyclic small molecules that inhibit influenza’s neuraminidase enzyme have been developed as commercially successful antivirals. Similarly potent inhibitors against prokaryotic or eukaryotic neuraminidases have yet to be described. Selective inhibitors of these latter neuraminidase isozymes may provide useful treatments for bacterial infections (such as cholera and pneumonia) as well as a variety of cancers and metabolic disorders. A conformationally-restricted scaffold may prove ideal for designing selective (and potent) inhibitors against these underexplored enzymes. As a proof of principle, one of our rigid bicyclic-sulfone archetypes is elaborated to a drug-like scaffold that is shown to inhibit viral, bacterial and human neuraminidase enzymes. | en_US |
| dc.description.proquestemail | mgbrant@uvic.ca | en_US |
| dc.description.scholarlevel | Graduate | en_US |
| dc.identifier.bibliographicCitation | M. G. Brant, C. M. Bromba and J. E. Wulff, The Journal of Organic Chemistry, 2010, 75, 6312-6315. | en_US |
| dc.identifier.bibliographicCitation | M. G. Brant and J. E. Wulff, Organic Letters, 2012, 14, 5876-5879. | en_US |
| dc.identifier.bibliographicCitation | M. G. Brant, J. N. Friedmann, C. G. Bohlken, A. G. Oliver and J. E. Wulff, Organic & Biomolecular Chemistry, 2015, 13, 4581-4588. | en_US |
| dc.identifier.bibliographicCitation | S. S. Y. Wong, M. G. Brant, C. Barr, A. G. Oliver and J. E. Wulff, Beilstein Journal of Organic Chemistry, 2013, 9, 1419-1425. | en_US |
| dc.identifier.bibliographicCitation | M. R. Richards, M. G. Brant, M. J. Boulanger, C. W. Cairo and J. E. Wulff, Medicinal Chemistry Communications, 2014, 5, 1483-1488. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1828/6339 | |
| dc.language | English | eng |
| dc.language.iso | en | en_US |
| dc.rights | Available to the World Wide Web | en_US |
| dc.rights.uri | http://creativecommons.org/publicdomain/zero/1.0/ | * |
| dc.subject | Bicyclic Sulfones | en_US |
| dc.subject | Neuraminidase | en_US |
| dc.subject | Enzyme Inhibitors | en_US |
| dc.subject | Influenza | en_US |
| dc.subject | Synthetic Methodology | en_US |
| dc.subject | 3-Sulfolene | en_US |
| dc.subject | Tamdem Reactions | en_US |
| dc.title | Synthesis of Bicyclic Sulfones: Inhibitors of Neuraminidase | en_US |
| dc.type | Thesis | en_US |