Abstract | PURPOSE: To study the reduction of RB90740 (1), a fused pyrazine mono-N- oxide that has an oxic:hypoxic cytotoxicity ratio of > 10 in a range of murine and human tumor cells in vitro. METHODS AND MATERIALS: Reduction of 1 has been initiated radiolytically and photochemically in aqueous solution and the products isolated and characterized by high performance liquid chromatography (HPLC). RESULTS: Radiolytic reduction of 1 leads to the formation of the 2-electron reduced product, 2. The stoichiometry of the reduction is pH dependent, increasing from 1 to 2 with increasing pH, but independent of the presence of formate or 2-methyl 2-propanol in the reduction mixture. A dimerization product, 3, is also found, which is produced in greater yields at lower pH (< 6). Photochemical reduction of 1 to 2 was also found to be facile. Photolysis of 1 also leads to a deoxyribonucleic acid cleavage reaction. CONCLUSION: Since 2 is not cytotoxic towards hypoxic cells at concentrations at which 1 is toxic, a probable candidate as the cytotoxic species under hypoxic conditions is the 1-electron reduced intermediate species.
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Authors | M A Naylor, B M Sutton, J Nolan, P O'Neill, E M Fielden, G E Adams, I J Stratford |
Journal | International journal of radiation oncology, biology, physics
(Int J Radiat Oncol Biol Phys)
Vol. 29
Issue 2
Pg. 333-7
(May 15 1994)
ISSN: 0360-3016 [Print] United States |
PMID | 8195029
(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
- Pyrazines
- RB 90740
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Topics |
- Animals
- Antineoplastic Agents
(metabolism, pharmacology)
- Cell Hypoxia
- Humans
- Hydrogen-Ion Concentration
- Mice
- Oxidation-Reduction
- Photochemistry
- Pyrazines
(chemistry, metabolism, pharmacology)
- Tumor Cells, Cultured
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