First Synthesis of an Aziridinyl Fused Pyrrolo[1,2-a]benzimidazole and Cytotoxicity Evaluation of Various Imidazobenzimidazolequinones Towards Human Normal and Cancer Cell Lines
Date
2011-07-13Author
Bonham, Sarah
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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.