Anti-tumour properties of novel diaziridinylquinones

This work is concerned with the synthesis and potential anti-tumour properties of novelDiaziridinylquinones. These types of compounds are usually activated by bioreductionto form cytotoxic species, which alkylate DNA and block cells in the G 2 /M phase of thecell cycle. However, the present studies have concentrated on compounds which appearto 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 stablemeta-phenol or an unstable para-phenol. The compounds were studied in detail usingDNA cross-linking, clonogenic, apoptosis and flow cytometry assays. Preliminarystudies on the protein tyrosine kinase (PTK) activity of the epidermal growth factorreceptor (EGF-R) showed that the |iM concentrations of the meta-phenol can reduce thePTK activity of purified EGF-R by 50%. The overall proposed mechanism is that thecytotoxic esters are cleaved by esterases to form reactive phenols. However, theenhanced toxicities of these compounds are not simply due to the differences in DNAcross-linking efficiencies. It is proposed that the phenols cross-link DNA and inhibitone or more tyrosine kinases.Preliminary tumour xenograft studies suggest that some acridine derivatives of PDZQhave a very high therapeutic index (Chapter 4). These compounds cross-link DNA butthere is no DNA-intercalation (from fluorescence, absorbance, DNA-unwinding and T mstudies). It is proposed that these compounds can be reduced within a cell and interactwith Topoisomerases.RH1 is scheduled for Phase I/II clinical trials and the final chapter of this thesis reportson the induction of apoptosis by this diaziridinylquinone. These studies used manydifferent biochemical/visual techniques to measure apoptosis. The general conclusionfrom this study is that although RH1 can induce apoptosis, the extent is stronglydependent on the cell line and it is only significant at relatively high concentrations ofdrug