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.
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Authors | M Jaffar, M A Naylor, N Robertson, S D Lockyer, R M Phillips, S A Everett, G E Adams, I J Stratford |
Journal | Anti-cancer drug design
(Anticancer Drug Des)
Vol. 13
Issue 2
Pg. 105-23
(Mar 1998)
ISSN: 0266-9536 [Print] United States |
PMID | 9524554
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Aziridines
- Indolequinones
- Indoles
- NAD(P)H Dehydrogenase (Quinone)
- apaziquone
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Topics |
- Aerobiosis
- Animals
- Antineoplastic Agents
(chemical synthesis, metabolism, pharmacology)
- Aziridines
(chemical synthesis, metabolism, pharmacology)
- Carcinoma, Non-Small-Cell Lung
(drug therapy)
- Cell Hypoxia
- Cell Line
- Cricetinae
- Cricetulus
- Fibroblasts
(drug effects)
- Humans
- Indolequinones
- Indoles
(chemical synthesis, metabolism, pharmacology)
- Lung Neoplasms
(drug therapy)
- NAD(P)H Dehydrogenase (Quinone)
(metabolism)
- Stereoisomerism
- Structure-Activity Relationship
- Tumor Cells, Cultured
(drug effects)
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