Anti-tumour properties of novel diaziridinylquinones

Di Francesco, AM

Abstract

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.

Citation

Di Francesco, A. Anti-tumour properties of novel diaziridinylquinones. (Thesis). Salford : University of Salford

• Thesis Type: Thesis
• Deposit Date: Oct 3, 2012
• Award Date: Jan 1, 2001