Hypoxia-selective antitumor agents. 13. Effects of acridine substitution on the hypoxia-selective cytotoxicity and metabolic reduction of the bis-bioreductive agent nitracrine N-oxide.

A series of nuclear-substituted derivatives of nitracrine N-oxide (2; a bis-bioreductive hypoxia-selective cytotoxin) were prepared and evaluated, seeking analogues of lower nitroacridine reduction potential. Disubstitution with Me or OMe groups at the 4- and 5-positions did not provide analogues with one-electron reduction potentials significantly lower than those of the corresponding monosubstituted derivatives (E(1) ca. -350 mV for both the 4-OMe and 4,5-diOMe compounds). This appears not to be due to a concomitant raising of the acridine pKa but to a lack of direct electronic effect of substituents in the ring not bearing the nitro group. Conversely, placing two OMe groups in the nitro-bearing ring does result in a substantial further lowering of reduction potential (the 2,4-diOMe analogue has an E(1) of -401 mV). The mono- and disubstituted N-oxides have substantially lower cytotoxicities than the parent nitracrine N-oxide 2 but generally retain very high hypoxic selectivity. The OMe-substituted N-oxides all showed greater metabolic stability than 2 in hypoxic AA8 cell cultures, and the 4-OMe compound 6 had improved activity in EMT6 multicellular spheroids suggesting that this metabolic stabilization may allow more efficient diffusion in tumor tissue. The parent compound 2 was selectively toxic to hypoxic cells in KHT tumors in vivo and clearly superior to nitracrine itself (although only at doses which would eventually be lethal to the host). The analogues of lower E(1), including 6, were not superior to 2 in vivo, indicating that metabolic stabilization of the nitro group is not alone sufficient to improve therapeutic utility.
AuthorsH H Lee, W R Wilson, D M Ferry, P van Zijl, S M Pullen, W A Denny
JournalJournal of medicinal chemistry (J Med Chem) Vol. 39 Issue 13 Pg. 2508-17 (Jun 21 1996) ISSN: 0022-2623 [Print] UNITED STATES
PMID8691448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Acridines
  • Antineoplastic Agents
  • Culture Media
  • C 684
  • Nitracrine
  • Acridines (chemical synthesis, metabolism, pharmacology, toxicity)
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Division (drug effects)
  • Cell Hypoxia
  • Cell Line
  • Cell Survival (drug effects)
  • Cricetinae
  • Cricetulus
  • Culture Media
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Mice, Inbred C3H
  • Molecular Structure
  • Nitracrine (analogs & derivatives, chemical synthesis, chemistry, metabolism, pharmacology)
  • Oxidation-Reduction
  • Tumor Cells, Cultured

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