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
The Gray Laboratory Cancer Research Trust, PO Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, UK
Clinical Oncology Unit, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK
December 1, 1997