The synthesis of novel indolequinones
thesisposted on 2016-07-19, 14:32 authored by Claire L. Norton
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 structures.
Publisher© Claire Louise Norton
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NotesA Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.