The concept of bioreductive prodrug chemotherapy is introduced in chapter 1. Tumour cell
hypoxia is a significant factor in limiting tumour growth control with conventional radiotherapy
and some chemotherapeutic agents. Following therapy these cells can repopulate and
cause a relapse of the cancer. On the other hand, hypoxia is unique to tumours, and is
therefore potentially exploitable. Bioreductive prodrugs are compounds in which a oxygen
inhibited redox-based bioactivation step triggers a reaction leading to a lethal intermediate.
The concept of bioreductive DNA alkylators and DNA topoisomerase 11 inhibitors is
The synthesis of model thiazolylindole compounds based on the natural product BE \0988
are discussed in chapter 2. Two strategies were employed for the construction of the
thiazolylindoles: the Hantzsch reaction; and nucleophilic substitution on 2-bromothiazole by
an indolyl anion. The synthesis of thiazolylindolequinone compounds are discussed in chapter 3. The quinone
C(5) position of the thiazolylindolequinone analogues was elaborated to provide a series of
cyclic and acyclic C(5)-amino derivatives.
Synthetic strategies towards the synthesis of indole-2-carboxylates are discussed in chapter 4.
The Moody-Rees and Cadogan-Sundberg reactions were employed to provide a synthesis of
the useful highly substituted indole .
The Brederek imidazole reaction (i.e., the reaction of a amidine and a-halo ketone) is
discussed in chapter 5. Application of the Brederek reaction was employed towards the
construction of the bisindole imidazole natural compounds, the nortopsentins.
The biological properties of the compounds of the compounds synthesised are discussed in
chapter 6. The compounds were tested for DNA topoisomerase 11 inhibitory activity and
cytotoxicity under a hypoxic environment.
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.