- Title
- The development of flow chemistry methodologies for the synthesis of potential anti-cancer agents
- Creator
- Hizartzidis, Lacey
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2015
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The discovery and development of more specific and targeted small molecule anti-cancer drugs over the last decade, has led to a movement away from the ‘one-size-fits-all’ approach for cancer treatment. The synthesis of such molecules requires control over both chemical reactivity and reaction conditions. Advances in the control over reaction parameters, such as temperature and pressure, through the emergence of technology such as flow reactors and automated synthesisers has accelerated method development and discovery. The utilisation of flow chemistry throughout this research has enabled the optimization and development of a variety of synthetic methodologies, some of which were not previously achievable by batch synthesis. These protocols have enabled access to numerous potential anti-cancer agents. Through examination of acrylonitrile-based small molecules, a number of libraries were tested for their cytotoxicity. Access to the quinolone-2-(1H)-one library was achieved by a sequential four component Ugi-Knoevenagel condensation to afford 11 analogues in moderate to good yields (49–71%). A variation of the Ugi reaction was also carried out, in which three component compounds were generated to afford an α-amino amide library of 12 analogues in good yields (51-70%) (Chapter 2). Two libraries of highly decorated norcantharidin analogues were accessed via a number of chemoselective flow hydrogenation reactions to afford an isoindole-7-carboxylic acid library (14 analogues) and 7-oxa-bicyclic[2.2.1]heptane library (20 analogues) in moderate to good yields (21–75%), Whilst no analogues in the isoindole-7-carboxylic acid library showed any significant biological activity, four compounds from the 7-oxa-bicyclic[2.2.1]heptane library were found to exhibit a >85% growth inhibition against one or more cancer cell lines with a concentration of 100 μM (Chapter 3). Hydrodehalogenation proved to be a significant challenge whilst conducting hydrogenation reactions using flow chemistry conditions. In an attempt to circumvent this problem, a series of catalysts were screened for their ability to effect reductions in the presence of halogens. It was identified the 5% Pt/C (sulfided) catalyst was effective in retaining halogen atoms for reductive aminations, nitro reductions and alkene reductions (Chapter 5). Flow chemistry protocols were developed for the Suzuki-Miyaura cross coupling of 5-formyl-2-furanly boronic acid and a range of aryl bromides to synthesise a small library of 13 furan-based biaryl analogues. Such compounds will be used in the future as building blocks towards the development of potential inhibitors of the Hedgehog signalling pathway, a promising new class of potential anti-cancer agents. (Chapter 6).
- Subject
- flow chemistry; chemistry; anti-cancer agents; norcantharidin
- Identifier
- http://hdl.handle.net/1959.13/1310026
- Identifier
- uon:21973
- Rights
- Copyright 2015 Lacey Hizartzidis
- Language
- eng
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| View Details Download | ATTACHMENT02 | Thesis | 8 MB | Adobe Acrobat PDF | View Details Download |