Free radical intermediates in the oxidation of flavone-8-acetic acid: possible involvement in its antitumour activity.
The sulphate radical (SO4.-), a model one-electron oxidant, reacts with the antitumour drug flavone-8-acetic acid (FFA) with the rate constant 9.1 x 10(8) dm3mol-1s-1 to yield an uncharged radical that reacts with oxygen (k approximately 1 x 10(9) dm3mol-1s-1). The oxidation of FAA by SO4.- in a steady-state system was found to release carbon dioxide with a yield of 96% relative to that of the SO.4-. The results are interpreted by fast (t1/2 < or = 1 microsecond) and efficient decarboxylation of the FAA radical cation, resulting in a carbon-centred radical. The reaction of the latter with oxygen is a possible source of radical-driven cytotoxic pathways, such as singlet oxygen formation via the Russell mechanism or H-abstraction from lipids. On the basis of the observations in the model system, a possible free radical mechanism for the antitumour action of the drug is suggested.
Candeias
L P
LP
Cancer Research Campaign Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex, UK.
Everett
S A
SA
Wardman
P
P
D000970:Antineoplastic Agents / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D002704:Chlorates; D005419:Flavonoids / Q000378:metabolism*; D005609:Free Radicals; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D011675:Pulse Radiolysis; D013053:Spectrophotometry; D013431:Sulfates / Q000378:metabolism*
D000970:Antineoplastic Agents; D002704:Chlorates; D005419:Flavonoids; D005609:Free Radicals; D013431:Sulfates; D002245:Carbon Dioxide; C049328:flavone acetic acid; C032706:sodium chlorate