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Hypoxia-selective antitumor agents. 4. Relationships between structure, physicochemical properties, and hypoxia-selective cytotoxicity for nitracrine analogues with varying side chains: the "iminoacridan hypothesis".

Abstract
The nitroacridine derivative nitracrine is a potent hypoxia-selective cytotoxin for mammalian cells in culture. In an attempt to modulate the degree of hypoxia selectivity among this class of compounds, we have studied a series of side-chain analogues of nitracrine. Both the electronic and steric properties of the side chain are shown to be important in determining the hypoxia selectivity of the compounds, by controlling the degree of aminoacridine/iminoacridan tautomerism. Studies with the repair-defective Chinese hamster cell line UV4 indicate that the cytotoxicity of all the compounds is due to nitro group reduction and subsequent macromolecular adduct formation. However, compounds such as the 9-amino derivative, which exist totally as the aminoacridine tautomer, form much less lethal lesions than the 9-alkylamino derivatives, which exist to varying degrees in the iminoacridan conformation. For the whole set of compounds, the degree of hypoxia-selective cytotoxicity correlates well with the proportion of iminoacridan tautomer present.
AuthorsW A Denny, G J Atwell, R F Anderson, W R Wilson
JournalJournal of medicinal chemistry (J Med Chem) Vol. 33 Issue 5 Pg. 1288-95 (May 1990) ISSN: 0022-2623 [Print] UNITED STATES
PMID2329552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Aminoacridines
  • Antineoplastic Agents
  • Nitracrine
Topics
  • Aminoacridines
  • Animals
  • Antineoplastic Agents (chemical synthesis, pharmacology)
  • Cell Hypoxia (drug effects)
  • Cell Line
  • Cell Survival (drug effects)
  • Chemical Phenomena
  • Chemistry
  • Cricetinae
  • Nitracrine (analogs & derivatives)
  • Structure-Activity Relationship

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