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|Title: ||The synthesis of novel indolequinones|
|Authors: ||Norton, Claire L.|
|Issue Date: ||1995|
|Publisher: ||© Claire Louise Norton|
|Abstract: ||Mitomycin C (MMC), obtained from Streptomyces caespitosus, a clinically useful
antitumour antibiotic, is the archetypical quinone bioreductive alkylating agent. The
reductive activation mechanism of MMC, involves quinone reduction sequentially
activating electrophilic sites in the drug molecule (C-l and C-lO for MMC). This
research project was designed to investigate the role of the C-lO in alkylation processes
by preparing compounds in which the electrophilicity at C-l is much reduced by
substituting a cyclopropane for the aziridine ring. The resulting pyrrolo[I,2-a]indole,
cyclopropamitosenes, could on reductive activation, by either 1- or 2-electron processes,
followed by elimination of the carbamate, generate a powerful electrophile capable of
alkylating DNA (or other nucleophiles) at C-lO ..
A range of compounds was prepared utilising the azidocinnamate decomposition route
to substituted indoles and an intramolecular [3 + 2] cycloaddition strategy was
employed to synthesise the pyrrolo[I,2-a]indole nucleus.
The rapid ring opening of cyclopropylcarbinyl radicals is briefly outlined. The
reduction-initiated ring opening of the cyclopropane ring is investigated, thereby
establishing its relevance to the potent bioreductive anticancer action of the
cyclopropamitosenes, novel analogues of MMC.
The design and synthesis of fused [I,2-a]indoles without the cyclopropane ring, is
examined for comparative purposes. The key step in the synthesis is the formation of
the [I,2-a ]indole nucleus via a radical cyclisation.
Biological data were recorded for the cyclopropamitosenes and correlated with their
|Description: ||A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.|
|Appears in Collections:||PhD Theses (Chemistry)|
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