Synthesis of Agents Potentially Useful in Cancer Chemotherapy

Abstract

A range of novel, potent, inhibitors of NAD(P)H quinone oxidoreductase 1 (NQO1) and NAD(P)H quinone oxidoreductase 2 (NQO2) were synthesised. The therapeutic utility of this could be three-fold: 1) Impairing tumour growth.2) Promoting the transient degradation of the p53 tumour suppressor protein in cells can enhance the activity of conventional anti-cancer drugs. 3) For probing the effects of NQO1 or NOQ2 inhibition within cells. The potential inhibitors were classified as three distinct groups based on the core structure, known as the triazoloacridinones (31), imidazoacridinones (131), and 4-hydroxycoumarins (182 - 195, 197 - 210). The syntheses of the triazoloacridinones (31) and imidazoacridinones (131) were achieved through divergent synthetic routes, so that a large variety of compounds could be made quickly, and economically. A selection of these were then modified to increase potency, improve water solubility, and lower toxicity. The final 4-hydroxycoumarin series (183, 190, 192, 199, 201, 215, 216) was first produced using existing methods. Later, a more desirable route was developed using the 'borrowing hydrogen' methodology, to improve upon the efficiency and yield. All three families of compounds were found to contain potent, nanomolar inhibitors of NQO1 and NQO2, which could inhibit the enzymes in cells, at non-toxic concentrations.

Date of Award	31 Dec 2011
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Ian Stratford (Supervisor) & Roger Whitehead (Supervisor)