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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.

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.
AuthorsM Jaffar, M A Naylor, N Robertson, S D Lockyer, R M Phillips, S A Everett, G E Adams, I J Stratford
JournalAnti-cancer drug design (Anticancer Drug Des) Vol. 13 Issue 2 Pg. 105-23 (Mar 1998) ISSN: 0266-9536 [Print] United States
PMID9524554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Aziridines
  • Indolequinones
  • Indoles
  • NAD(P)H Dehydrogenase (Quinone)
  • apaziquone
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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