5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents

structure-cytotoxicity in vitro

M Jaffar, M A Naylor, N Robertson, S D Lockyer, R M Phillips, S A Everett, G E Adams, I J Stratford

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.

Original languageEnglish
Pages (from-to)105-123
Number of pages19
JournalAnti-Cancer Drug Design
Volume13
Issue number2
Publication statusPublished - Mar 1998
Externally publishedYes

Fingerprint

apaziquone
Cytotoxicity
NAD(P)H Dehydrogenase (Quinone)
Toxicity
Electron affinity
Electrons
Enzyme Activation
2-methylindole
1-methylindole
In Vitro Techniques
Hypoxia
Tumor Cell Line
Tumors
Chemical activation
Cells

Cite this

@article{93f0cae497614044ad806895c2d5c840,
title = "5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents: structure-cytotoxicity in vitro",
abstract = "A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.",
keywords = "Aerobiosis, Animals, Antineoplastic Agents/chemical synthesis, Aziridines/chemical synthesis, Carcinoma, Non-Small-Cell Lung/drug therapy, Cell Hypoxia, Cell Line, Cricetinae, Cricetulus, Fibroblasts/drug effects, Humans, Indolequinones, Indoles/chemical synthesis, Lung Neoplasms/drug therapy, NAD(P)H Dehydrogenase (Quinone)/metabolism, Stereoisomerism, Structure-Activity Relationship, Tumor Cells, Cultured/drug effects",
author = "M Jaffar and Naylor, {M A} and N Robertson and Lockyer, {S D} and Phillips, {R M} and Everett, {S A} and Adams, {G E} and Stratford, {I J}",
year = "1998",
month = "3",
language = "English",
volume = "13",
pages = "105--123",
journal = "Anti-Cancer Drug Design",
issn = "0266-9536",
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}

5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents : structure-cytotoxicity in vitro. / Jaffar, M; Naylor, M A; Robertson, N; Lockyer, S D; Phillips, R M; Everett, S A; Adams, G E; Stratford, I J.

In: Anti-Cancer Drug Design, Vol. 13, No. 2, 03.1998, p. 105-123.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents

T2 - structure-cytotoxicity in vitro

AU - Jaffar, M

AU - Naylor, M A

AU - Robertson, N

AU - Lockyer, S D

AU - Phillips, R M

AU - Everett, S A

AU - Adams, G E

AU - Stratford, I J

PY - 1998/3

Y1 - 1998/3

N2 - A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.

AB - A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.

KW - Aerobiosis

KW - Animals

KW - Antineoplastic Agents/chemical synthesis

KW - Aziridines/chemical synthesis

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Cell Hypoxia

KW - Cell Line

KW - Cricetinae

KW - Cricetulus

KW - Fibroblasts/drug effects

KW - Humans

KW - Indolequinones

KW - Indoles/chemical synthesis

KW - Lung Neoplasms/drug therapy

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

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Tumor Cells, Cultured/drug effects

M3 - Article

VL - 13

SP - 105

EP - 123

JO - Anti-Cancer Drug Design

JF - Anti-Cancer Drug Design

SN - 0266-9536

IS - 2

ER -