ARAN - Access to Research at NUI Galway

First Synthesis of an Aziridinyl Fused Pyrrolo[1,2-a]benzimidazole and Cytotoxicity Evaluation of Various Imidazobenzimidazolequinones Towards Human Normal and Cancer Cell Lines

ARAN - Access to Research at NUI Galway

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dc.contributor.advisor Aldabbagh, Fawaz
dc.contributor.author Bonham, Sarah
dc.date.accessioned 2012-03-09T14:28:32Z
dc.date.available 2012-11-21T15:33:22Z
dc.date.issued 2011-07-13
dc.identifier.uri http://hdl.handle.net/10379/2599
dc.description.abstract Chapter 1 provides a review of aziridine containing anti-tumour agents and some key syntheses of the aziridinomitosene skeleton. A novel protocol for aziridine ring fusion is described leading to the preparation of the first aziridinyl fused pyrrolo[1,2-a]benzimidazole. This diazole analogue of aziridinomitosene was formed via selective lithiation of the aziridine leading to an anionic aromatic ipso-substitution onto the benzimidazole-2-position. A non-fused aziridine containing benzimidazole is also prepared for cytotoxicity comparisons. Both novel aziridine compounds are evaluated towards a human normal skin fibroblast cell line (GM00637) and two breast cancer cell lines (MCF-7) and (HCC1937). The latter is breast cancer tumour suppressor gene deficient (BRCA1 deficient), and showed hypersensitivity to mitomycin C (MMC). BRCA1 is reported to play a key role in the repair of DNA damage. Both aziridine benzimidazole compounds are more cytotoxic towards the breast cancer cell lines than the normal cell line. The evidence provided indicates that different pathways mediate cellular response to benzimidazole containing-aziridine compounds compared to MMC. Chapter 2 begins with an introduction to the enzyme-directed approach to chemotherapy, and a review of polycyclic quinones. A series of dialicyclic ring fused imidazo[5,4-f]benzimidazolequinones were evaluated using the MTT assay towards two human cancer cell lines; cervical (HeLa) and prostate (DU145) and a normal cell line (GM00637). Dipyrido[5,4-f]imidazobenzimidazolequinone is found to possess similar toxicity to its [4,5-f] isomer, while an oxygen atom in the alicyclic fused ring ([1,4]oxazino) is found to dramatically increase toxicity towards all three cell lines. The toxicity of pyrido-fused compounds is found to be less than the N-butyl analogues, and increasing the alicyclic ring size from five to seven membered reduces activity. Iminoquinone is found to be ~12 times more toxic towards prostate cancer than towards the normal cell line. The iminoquinone shows a moderate to strong correlation towards cell lines expressing high levels of NQO1 activity, confirmed by further testing at the National Cancer Institute (NCI-60 program). Chapter 3 describes in detail the experimental procedures for Chapters 1 and 2. en_US
dc.subject Chemistry en_US
dc.title First Synthesis of an Aziridinyl Fused Pyrrolo[1,2-a]benzimidazole and Cytotoxicity Evaluation of Various Imidazobenzimidazolequinones Towards Human Normal and Cancer Cell Lines en_US
dc.type Thesis en_US
dc.contributor.funder Science Foundation Ireland en_US
dc.local.final Yes en_US

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