Reduction of antitumour mitosenes in non-aqueous and aqueous environment. An electron spin resonance and cyclic voltammetry study.
Chemical reduction of mitosenes under aerobic conditions in DMSO showed characteristic ESR signals of the mitosene derived semiquinone free radicals. However, these signals diminished strongly upon addition of water to the reaction mixture, indicating a short lifetime of the mitosene semiquinone free radicals under aqueous conditions. In addition, enzymatic one-electron reduction of these mitosenes with either xanthine oxidase or purified NADPH cytochrome P450 reductase under anaerobic conditions showed no signals of the mitosene semiquinone free radicals. Subsequent cyclic voltammetry measurements demonstrated facilitation of the further one-electron reduction of the mitosene semiquinone free radicals in the presence of water in comparison with non-aqueous conditions. The present results strongly suggest that in the presence of water relatively stable hydroquinones are formed upon reduction of mitosenes. Consequently, the steady state concentrations of mitosene semiquinone free radicals will be lowered substantially in aqueous environment. Thus under physiological conditions, two-electron reduction and formation of the mitosene hydroquinone might be important in processes leading to DNA alkylation by these mitosenes.
Maliepaard
M
M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, The Netherlands.
De Mol
N J
NJ
Janssen
L H
LH
Goeptar
A R
AR
Te Koppele
J M
JM
Vermeulen
N P
NP
Verboom
W
W
Reinhoudt
D N
DN
D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001894:Borohydrides / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004121:Dimethyl Sulfoxide; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D008937:Mitomycins / Q000737:chemistry* / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry; D051381:Rats; D012996:Solutions; D014867:Water; D014969:Xanthine Oxidase / Q000378:metabolism
D000970:Antineoplastic Agents; D001894:Borohydrides; D005609:Free Radicals; D008937:Mitomycins; D011809:Quinones; D012996:Solutions; D014867:Water; C046001:mitosene; C025364:sodium borohydride; D004247:DNA; D014969:Xanthine Oxidase; D009251:NADPH-Ferrihemoprotein Reductase; D004121:Dimethyl Sulfoxide