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Pharmacological and biological evaluation of a series of substituted 1,4 naphthoquinone bioreductive drugs.

By Roger M. Phillips, Paul M. Loadman, Derek J. Maitland, Steven D. Shnyder, M. Jaffar, Gillian Steans, Patricia A. Cooper, Amanda D. Race, A.V. Patterson and I.J. Stratford

Abstract

NoThe indolequinone compound EO9 has good pharmacodynamic properties in terms of bioreductive activation and selectivity for either NAD(P)H:quinone oxidoreductase-1 (NQO1)-rich aerobic or NQO1-deficient hypoxic cells. However, its pharmacokinetic properties are poor and this fact is believed to be a major reason for EO9's lack of clinical efficacy. The purpose of this study was to develop quinone-based bioreductive drugs that retained EO9's good properties, in terms of bioreductive activation, but have improved pharmacokinetic properties. Out of 11 naphthoquinone compounds evaluated, 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (compound 2), 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (compound 3), and 2-aziridinyl-6-hydroxymethyl-1,4-naphthoquinone (compound 11) were selected for further evaluation based on good substrate specificity for NQO1 and selectivity towards NQO1-rich cells in vitro. Compound 3 was of particular interest as it also demonstrated selectivity for NQO1-rich cells under hypoxic conditions. Compound 3 was not metabolised by murine whole blood in vitro (in contrast to compounds 2, 11 and EO9) and pharmacokinetic studies in non-tumour-bearing mice in vivo (at the maximum soluble dose of 60 mg kg¿1 administered intraperitoneally) demonstrated significant improvements in plasma half-life (16.2 min) and AUC values (22.5 ¿M h) compared to EO9 (T1/2 = 1.8 min, AUC = 0.184 ¿M h). Compound 3 also demonstrated significant anti-tumour activity against H460 and HCT-116 human tumour xenografts in vivo, whereas EO9 was inactive against these tumours. In conclusion, compound 3 is a promising lead compound that may target both aerobic and hypoxic fractions of NQO1-rich tumours and further studies to elucidate its mechanism of action and improve solubility are warranted

Topics: NQO1, Hypoxia, Bioreductive drugs, Naphthoquinones
Year: 2004
DOI identifier: 10.1016/j.bcp.2004.08.007
OAI identifier: oai:bradscholars.brad.ac.uk:10454/3804
Provided by: Bradford Scholars
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