Bioreductive activation of a series of analogues of 5-aziridinyl-3-hydroxymethyl-1-methyl-2-[1H-indole-4, 7-dione] prop-beta-en-alpha-ol (EO9) by human DT-diaphorase

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Abstract

The enzyme DT-diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) is believed to be a good target for enzyme-directed bioreductive drug development because elevated levels of enzyme activity have been described in several human tumour types and it plays a key role in the bioreductive activation of several quinone-based anticancer drugs. As part of an ongoing program to develop new bioreductive drugs, the ability of a series of indoloquinone compounds to serve as substrates for and to be bioreductively activated by purified recombinant human DTD was investigated. Of the seven compounds evaluated, EO9, EO68 and EO4 were substrates for human DTD, but only EO4 was reduced to a DNA cross-linking species, and this DNA damage was both concentration dependent and inhibited by dicoumarol. A broad spectrum of chemosensitivity was observed in the H460 non-small cell lung cancer cell line, with the most potent compounds being EO4 (IC50 = 23.9 nM), EO9 (IC50 = 34.5 nM) and EO68 (IC50 = 37.8 nM). Relatively minor structural changes resulted in major changes in both substrate specificity and cytotoxic potency. Comparative chemosensitivity studies demonstrated that EO4, EO9 and EO68 are preferentially toxic towards DTD-rich H460 cells compared with DTD-deficient H596 cells (ratio of IC50 values for H596 cells to H460 cells were 113.8, 92.2 and 103.9 respectively). In conclusion, this study has identified two new compounds that are substrates for human DTD, one of which (EO4) is reduced to a DNA cross-linking species. Further studies in a broad panel of cell lines and human tumour xenografts are warranted for EO4 and EO68 based upon the result of this study.

LanguageEnglish
Pages1711-8
Number of pages8
JournalBiochemical Pharmacology
Volume52
Issue number11
DOIs
Publication statusPublished - 13 Dec 1996
Externally publishedYes

Fingerprint

apaziquone
NAD(P)H Dehydrogenase (Quinone)
Chemical activation
Inhibitory Concentration 50
Cells
Substrates
Indolequinones
Tumors
DNA
Pharmaceutical Preparations
Dicumarol
Enzymes
Poisons
Enzyme activity
Heterografts
Substrate Specificity
Tumor Cell Line
Non-Small Cell Lung Carcinoma
DNA Damage
Cell Line

Cite this

@article{fd1f11f12adc4ca7b56378de79338685,
title = "Bioreductive activation of a series of analogues of 5-aziridinyl-3-hydroxymethyl-1-methyl-2-[1H-indole-4, 7-dione] prop-beta-en-alpha-ol (EO9) by human DT-diaphorase",
abstract = "The enzyme DT-diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) is believed to be a good target for enzyme-directed bioreductive drug development because elevated levels of enzyme activity have been described in several human tumour types and it plays a key role in the bioreductive activation of several quinone-based anticancer drugs. As part of an ongoing program to develop new bioreductive drugs, the ability of a series of indoloquinone compounds to serve as substrates for and to be bioreductively activated by purified recombinant human DTD was investigated. Of the seven compounds evaluated, EO9, EO68 and EO4 were substrates for human DTD, but only EO4 was reduced to a DNA cross-linking species, and this DNA damage was both concentration dependent and inhibited by dicoumarol. A broad spectrum of chemosensitivity was observed in the H460 non-small cell lung cancer cell line, with the most potent compounds being EO4 (IC50 = 23.9 nM), EO9 (IC50 = 34.5 nM) and EO68 (IC50 = 37.8 nM). Relatively minor structural changes resulted in major changes in both substrate specificity and cytotoxic potency. Comparative chemosensitivity studies demonstrated that EO4, EO9 and EO68 are preferentially toxic towards DTD-rich H460 cells compared with DTD-deficient H596 cells (ratio of IC50 values for H596 cells to H460 cells were 113.8, 92.2 and 103.9 respectively). In conclusion, this study has identified two new compounds that are substrates for human DTD, one of which (EO4) is reduced to a DNA cross-linking species. Further studies in a broad panel of cell lines and human tumour xenografts are warranted for EO4 and EO68 based upon the result of this study.",
keywords = "Antineoplastic Agents/metabolism, Aziridines/metabolism, Biotransformation, Cell Survival/drug effects, DNA/metabolism, Humans, Indolequinones, Indoles/metabolism, Kinetics, NAD(P)H Dehydrogenase (Quinone)/metabolism, Structure-Activity Relationship, Tumor Cells, Cultured",
author = "Phillips, {R M}",
year = "1996",
month = "12",
day = "13",
doi = "10.1016/S0006-2952(96)00521-7",
language = "English",
volume = "52",
pages = "1711--8",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "11",

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TY - JOUR

T1 - Bioreductive activation of a series of analogues of 5-aziridinyl-3-hydroxymethyl-1-methyl-2-[1H-indole-4, 7-dione] prop-beta-en-alpha-ol (EO9) by human DT-diaphorase

AU - Phillips, R M

PY - 1996/12/13

Y1 - 1996/12/13

N2 - The enzyme DT-diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) is believed to be a good target for enzyme-directed bioreductive drug development because elevated levels of enzyme activity have been described in several human tumour types and it plays a key role in the bioreductive activation of several quinone-based anticancer drugs. As part of an ongoing program to develop new bioreductive drugs, the ability of a series of indoloquinone compounds to serve as substrates for and to be bioreductively activated by purified recombinant human DTD was investigated. Of the seven compounds evaluated, EO9, EO68 and EO4 were substrates for human DTD, but only EO4 was reduced to a DNA cross-linking species, and this DNA damage was both concentration dependent and inhibited by dicoumarol. A broad spectrum of chemosensitivity was observed in the H460 non-small cell lung cancer cell line, with the most potent compounds being EO4 (IC50 = 23.9 nM), EO9 (IC50 = 34.5 nM) and EO68 (IC50 = 37.8 nM). Relatively minor structural changes resulted in major changes in both substrate specificity and cytotoxic potency. Comparative chemosensitivity studies demonstrated that EO4, EO9 and EO68 are preferentially toxic towards DTD-rich H460 cells compared with DTD-deficient H596 cells (ratio of IC50 values for H596 cells to H460 cells were 113.8, 92.2 and 103.9 respectively). In conclusion, this study has identified two new compounds that are substrates for human DTD, one of which (EO4) is reduced to a DNA cross-linking species. Further studies in a broad panel of cell lines and human tumour xenografts are warranted for EO4 and EO68 based upon the result of this study.

AB - The enzyme DT-diaphorase (NAD(P)H:quinone acceptor oxidoreductase, EC 1.6.99.2.; DTD) is believed to be a good target for enzyme-directed bioreductive drug development because elevated levels of enzyme activity have been described in several human tumour types and it plays a key role in the bioreductive activation of several quinone-based anticancer drugs. As part of an ongoing program to develop new bioreductive drugs, the ability of a series of indoloquinone compounds to serve as substrates for and to be bioreductively activated by purified recombinant human DTD was investigated. Of the seven compounds evaluated, EO9, EO68 and EO4 were substrates for human DTD, but only EO4 was reduced to a DNA cross-linking species, and this DNA damage was both concentration dependent and inhibited by dicoumarol. A broad spectrum of chemosensitivity was observed in the H460 non-small cell lung cancer cell line, with the most potent compounds being EO4 (IC50 = 23.9 nM), EO9 (IC50 = 34.5 nM) and EO68 (IC50 = 37.8 nM). Relatively minor structural changes resulted in major changes in both substrate specificity and cytotoxic potency. Comparative chemosensitivity studies demonstrated that EO4, EO9 and EO68 are preferentially toxic towards DTD-rich H460 cells compared with DTD-deficient H596 cells (ratio of IC50 values for H596 cells to H460 cells were 113.8, 92.2 and 103.9 respectively). In conclusion, this study has identified two new compounds that are substrates for human DTD, one of which (EO4) is reduced to a DNA cross-linking species. Further studies in a broad panel of cell lines and human tumour xenografts are warranted for EO4 and EO68 based upon the result of this study.

KW - Antineoplastic Agents/metabolism

KW - Aziridines/metabolism

KW - Biotransformation

KW - Cell Survival/drug effects

KW - DNA/metabolism

KW - Humans

KW - Indolequinones

KW - Indoles/metabolism

KW - Kinetics

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

KW - Structure-Activity Relationship

KW - Tumor Cells, Cultured

U2 - 10.1016/S0006-2952(96)00521-7

DO - 10.1016/S0006-2952(96)00521-7

M3 - Article

VL - 52

SP - 1711

EP - 1718

JO - Biochemical Pharmacology

T2 - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 11

ER -