The University of ManchesterButhaina Hussein Khalid HusseinDoctor of PhilosophySynthesis and evaluation of novel NQO2 inhibitors2016Abstract(NRH): quinone oxidoreductase 2 (NQO2) is one of the enzymes that belongs to the mammalian quinone reductases (QRs) enzyme family that is responsible for the two-electron reduction of quinone to hydroquinone. There is evidence that NQO2 is associated with cancer initiation via the production of ROS during quinone metabolism. Interest increased in finding novel NQO2 inhibitors, which show good selectivity and potency. The aim of this project is to design, synthesise and evaluate novel and selective NQO2 inhibitors as potential anticancer candidates, with low toxicity and good stability at physiological pH.A library of analogues containing the 4-aminoquinoline scaffold has been computationally docked in the crystal structure of the reduced and oxidized NQO2 (PDB code 4U7F and 4FGJ, respectively) using Gold suite (version 5.3). The results of the molecular docking showed an increase in the binding affinity with hydrazone derivatives, compared to the hydrazine, hydrazide, and amine analogues. Introducing an aromatic ring such as phenyl or pyridine at position 2 makes a noticeable increase in the docking score. Twenty-one compounds from the library were synthesized, which involved condensation of p-anisidine with Meldrum's acid and trimethyl orthoacetate or trimethyl orthobenzoate to produce the 4-hydrazine-quinoline scaffold.The potency of the synthesized compounds to inhibit the NQO2 enzyme was determined and measured spectrophotometrically using 2,6-dichlorophenolindophenol as a substrate. These compounds showed potent NQO2 inhibition activity with IC50 values in the low nano-molar concentrations.The selectivity of the synthesised compounds toward NQO2 rather than NQO1 has been tested. A few compounds showed activity toward NQO1, however with high micromolar concentrations. The role of NQO2 inhibitors was also investigated as antimalarial leads where a group of 4-hydrazonequinoline and furan-amidines and their analogues have been synthesised and shown to be active against the malaria parasite Plasmodium falciparum.
|Date of Award||1 Aug 2018|
- The University of Manchester
|Supervisor||Sally Freeman (Supervisor), Ian Stratford (Supervisor), Roger Whitehead (Supervisor) & Karen Nolan (Supervisor)|
- Cancer, 4-Aminoquinoline, Malaria, Hydrazone, Furanamidine, Synthesis