The relevance of secondary radicals in the mode of action of anthralin.
The formation of free radicals during the reaction of anthralin analogues with peroxidizing polyunsaturated lipids was monitored by ESR spectroscopy. The biological effect of the different compounds was assessed by their ability to inhibit respiration of cultured human keratinocytes. C(10)-monosubstituted analogues of anthralin exhibited a strong antirespiratory effect and produced a cascade of radicals. Abstraction of the hydrogen atom at C(10) led to the generation of primary radicals which further decomposed into secondary radicals similar to those observed with anthralin itself. 10, 10'-disubstituted analogues of anthralin did not form any paramagnetic species during reaction with peroxidizing lipids while decomposition of a 2,7-disubstituted anthralin derivative under the same conditions resulted in primary, but not secondary radical species. Since both types of disubstituted analogues are devoid of antirespiratory activity we postulate that the antimitochondrial and thus antiproliferative activity of anthralin and its analogues is associated with their capacity to form secondary radicals during their decomposition.
Lambelet
P
P
Nestlé Research Centre, Nestec, Lausanne, Switzerland.
Ducret
F
F
Löliger
J
J
Maignan
J
J
Reichert
U
U
Shroot
B
B
D000875:Anthralin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000378:metabolism*; D002478:Cells, Cultured; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects
D005609:Free Radicals; D005973:Glutamine; D002245:Carbon Dioxide; D000875:Anthralin