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

Roger M Phillips, Mohammed Jaffar, Derek J Maitland, Paul M Loadman, Steven D Shnyder, Gillian Steans, Patricia A Cooper, Amanda Race, Adam V Patterson, Ian J Stratford

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Abstract

The 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 microM h) compared to EO9 (T(1/2) = 1.8 min, AUC = 0.184 microM 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.

Original languageEnglish
Pages (from-to)2107-16
Number of pages10
JournalBiochemical Pharmacology
Volume68
Issue number11
DOIs
Publication statusPublished - 1 Dec 2004
Externally publishedYes

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apaziquone
Pharmacology
Pharmacokinetics
Tumors
Pharmaceutical Preparations
Area Under Curve
Indolequinones
Neoplasms
Bearings (structural)
Chemical activation
Pharmacodynamics
Lead compounds
Naphthoquinones
Substrate Specificity
Heterografts
NAD
Solubility
Half-Life
1,4-naphthoquinone
Oxidoreductases

Cite this

Phillips, R. M., Jaffar, M., Maitland, D. J., Loadman, P. M., Shnyder, S. D., Steans, G., ... Stratford, I. J. (2004). Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs. Biochemical Pharmacology, 68(11), 2107-16. https://doi.org/10.1016/j.bcp.2004.08.007
Phillips, Roger M ; Jaffar, Mohammed ; Maitland, Derek J ; Loadman, Paul M ; Shnyder, Steven D ; Steans, Gillian ; Cooper, Patricia A ; Race, Amanda ; Patterson, Adam V ; Stratford, Ian J. / Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs. In: Biochemical Pharmacology. 2004 ; Vol. 68, No. 11. pp. 2107-16.
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abstract = "The 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 microM h) compared to EO9 (T(1/2) = 1.8 min, AUC = 0.184 microM 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.",
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Phillips, RM, Jaffar, M, Maitland, DJ, Loadman, PM, Shnyder, SD, Steans, G, Cooper, PA, Race, A, Patterson, AV & Stratford, IJ 2004, 'Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs', Biochemical Pharmacology, vol. 68, no. 11, pp. 2107-16. https://doi.org/10.1016/j.bcp.2004.08.007

Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs. / Phillips, Roger M; Jaffar, Mohammed; Maitland, Derek J; Loadman, Paul M; Shnyder, Steven D; Steans, Gillian; Cooper, Patricia A; Race, Amanda; Patterson, Adam V; Stratford, Ian J.

In: Biochemical Pharmacology, Vol. 68, No. 11, 01.12.2004, p. 2107-16.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs

AU - Phillips, Roger M

AU - Jaffar, Mohammed

AU - Maitland, Derek J

AU - Loadman, Paul M

AU - Shnyder, Steven D

AU - Steans, Gillian

AU - Cooper, Patricia A

AU - Race, Amanda

AU - Patterson, Adam V

AU - Stratford, Ian J

PY - 2004/12/1

Y1 - 2004/12/1

N2 - The 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 microM h) compared to EO9 (T(1/2) = 1.8 min, AUC = 0.184 microM 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.

AB - The 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 microM h) compared to EO9 (T(1/2) = 1.8 min, AUC = 0.184 microM 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.

KW - Animals

KW - Antineoplastic Agents/pharmacokinetics

KW - Aziridines/metabolism

KW - Disease Models, Animal

KW - Drug Screening Assays, Antitumor

KW - Drug Stability

KW - Female

KW - Humans

KW - Hypoxia/metabolism

KW - Indolequinones/metabolism

KW - Mice

KW - NAD(P)H Dehydrogenase (Quinone)/metabolism

KW - Naphthoquinones/metabolism

KW - Neoplasm Transplantation

KW - Neoplasms, Experimental/drug therapy

KW - Substrate Specificity

KW - Tumor Cells, Cultured

KW - Xenograft Model Antitumor Assays

U2 - 10.1016/j.bcp.2004.08.007

DO - 10.1016/j.bcp.2004.08.007

M3 - Article

VL - 68

SP - 2107

EP - 2116

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 11

ER -