A range of novel and potent NQO1 and NQO2 inhibitors were synthesised. A series of 4-hydroxycoumarin analogues were prepared and assayed against NQO1. Furthermore, a more efficient synthetic route was developed by employing the “borrowing hydrogen” methodology. All the synthetic unsymmetrical dicoumarol analogues were novel and potent NQO1 inhibitors with IC50¬ values in the nanomolar range. The most potent analogues were non-toxic against the non-small cell lung cancer cell line, A549.The potential NQO2 inhibitors were classified in three different groups based on their core structure: 4-aminoquinolines, 7-chloro-4-aminoquinolines and 6-methoxy-4-aminoquinolines, where each group comprises of the following four subsets: the N-phenylated-, N-benzylated-, N-benzoylated- and the 4-hydrazinoquinoline analogues. Most of the quinoline analogues were found to be potent NQO2 inhibitors with IC50 values in the nanomolar range with the exception of the N-phenylated subset. The most potent analogues were toxic against the human breast adenocarcinoma cell line, MDA-MB-468.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:607418 |
| Date | January 2014 |
| Creators | Chee, Soo Mei |
| Contributors | Stratford, Ian; Whitehead, Roger |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/design-synthesis-and-biological-evaluation-of-the-novel-inhibitors-of-enzymes-nqo1-and-nqo2(14689fca-4a77-4102-8f55-49c90be6fa72).html |
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