This work is concerned with the synthesis and potential anti-tumour properties of novel Diaziridinylquinones. These types of compounds are usually activated by bioreduction to form cytotoxic species, which alkylate DNA and block cells in the G 2 /M phase of the cell cycle. However, the present studies have concentrated on compounds which appear to function by other mechanisms. Certain phenol/ester derivatives of PDZQ (2,5-diaziridinyl-3-phenyl-l,4-benzoquinone) were significantly more cytotoxic than PDZQ in all of the cell lines investigated (Chapter 3). The esters were cleaved by esterases to form a highly cytotoxic stable meta-phenol or an unstable para-phenol. The compounds were studied in detail using DNA cross-linking, clonogenic, apoptosis and flow cytometry assays. Preliminary studies on the protein tyrosine kinase (PTK) activity of the epidermal growth factor receptor (EGF-R) showed that the |iM concentrations of the meta-phenol can reduce the PTK activity of purified EGF-R by 50%. The overall proposed mechanism is that the cytotoxic esters are cleaved by esterases to form reactive phenols. However, the enhanced toxicities of these compounds are not simply due to the differences in DNA cross-linking efficiencies. It is proposed that the phenols cross-link DNA and inhibit one or more tyrosine kinases. Preliminary tumour xenograft studies suggest that some acridine derivatives of PDZQ have a very high therapeutic index (Chapter 4). These compounds cross-link DNA but there is no DNA-intercalation (from fluorescence, absorbance, DNA-unwinding and T m studies). It is proposed that these compounds can be reduced within a cell and interact with Topoisomerases. RH1 is scheduled for Phase I/II clinical trials and the final chapter of this thesis reports on the induction of apoptosis by this diaziridinylquinone. These studies used many different biochemical/visual techniques to measure apoptosis. The general conclusion from this study is that although RH1 can induce apoptosis, the extent is strongly dependent on the cell line and it is only significant at relatively high concentrations of drug.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:402645 |
| Date | January 2001 |
| Creators | Di Francesco, Angela Maria |
| Publisher | University of Salford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://usir.salford.ac.uk/26638/ |
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