Bis-bioreductive agents as hypoxia-selective cytotoxins: nitracrine N-oxide.

Abstract

Drugs with two reducible centers, both of which must be metabolized by oxygen-inhibitable processes for full activation ("bis-bioreductive agents"), offer potential for the development of hypoxia-selective cytotoxins with improved oxygen sensitivity. The sidechain N-oxide (1-NCO) of the (mono)bioreductive agent nitracrine (1-NC) has been synthesized and evaluated as a potential example of such an approach. The association constant for reversible DNA binding of 1-NCO was 15-fold lower than that of 1-NC, as measured by equilibrium dialysis in a low ionic strength buffer, indicating that the N-oxide has the potential to act as a less toxic pro-drug of 1-NC. Cell uptake and aerobic cytotoxicity of 1-NCO were much lower than for 1-NC whereas its hypoxic selectivity as a cytotoxin was greatly increased. In stirred suspension cultures of AA8 cells, pure (less than 0.02% 1-NC) 1-NCO was 1000-1500 times more potent under hypoxia than in 20% O2. For 1-NC the corresponding ratio was 10 +/- 1. 1-NCO had greater hypoxic selectivity in this system than misonidazole (ratio 11), RSU 1069 (ratio 25), 8Me-5NQ (ratio 60), or SR 4233 (ratio 80). Studies of 1-NCO metabolism indicate rapid, O2-inhibited reduction to 1-NC. The data are consistent with a two-step bioactivation mechanism, with reduction of the N-oxide generating a DNA intercalator of increased binding affinity, followed by reduction of the nitro group of this DNA-targeted cytotoxin to form reactive cytotoxic metabolites.

• Authors: W R Wilson, P Van Zijl, W A Denny
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 22 Issue 4 Pg. 693-6 ( 1992) ISSN: 0360-3016 [Print] United States
• PMID: 1544839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Prodrugs
• C 684
• Nitracrine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Hypoxia
• Cell Survival (drug effects)
• Cricetinae
• In Vitro Techniques
• Nitracrine (analogs & derivatives, chemical synthesis, pharmacology)
• Prodrugs (chemical synthesis, pharmacology)
• Time Factors