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5-Substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione[prop-2-en-1-o l (EO9, NSC 282459) and their regioisomers as hypoxia-selective agents: structure-cytotoxicity in vitro

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A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl]-2-[1H-indole-4,7-dione[prope-2-en-1 -ol (EO9, NSC 282459) 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 substituents (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 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.

Key words: bioreductive agents/EO9 regioisomers, hypoxia-selective/indoloquinone/prodrugs
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Document Type: Research Article

Affiliations: 1: Corresponding author 2: The Gray Laboratory Cancer Research Trust, PO Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, UK 3: Clinical Oncology Unit, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK

Publication date: December 1, 1997

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