Design, Synthesis and Biological Evaluation of the Novel Inhibitors of Enzymes NQO1 and NQO2

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Abstract

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.

Keyword(s)

NQO1, NQO2, synthesis, "borrowing hydrogen" methodology, MTT, enzyme assay.

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