Redox cycling of potential antitumor aziridinyl quinones.
The formation of reactive oxygen intermediates (ROI) during redox cycling of newly synthesized potential antitumor 2,5-bis (1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied by assaying the production of ROI (superoxide, hydroxyl radical, and hydrogen peroxide) by xanthine oxidase in the presence of BABQ derivatives. At low concentrations (< 10 microM) some BABQ derivatives turned out to inhibit the production of superoxide and hydroxyl radicals by xanthine oxidase, while the effect on the xanthine-oxidase-induced production of hydrogen peroxide was much less pronounced. Induction of DNA strand breaks by reactive oxygen species generated by xanthine oxidase was also inhibited by BABQ derivatives. The DNA damage was comparable to the amount of hydroxyl radicals produced. The inhibiting effect on hydroxyl radical production can be explained as a consequence of the lowered level of superoxide, which disrupts the Haber-Weiss reaction sequence. The inhibitory effect of BABQ derivatives on superoxide formation correlated with their one-electron reduction potentials: BABQ derivatives with a high reduction potential scavenge superoxide anion radicals produced by xanthine oxidase, leading to reduced BABQ species and production of hydrogen peroxide from reoxidation of reduced BABQ. This study, using a unique series of BABQ derivatives with an extended range of reduction potentials, demonstrates that the formation of superoxide and hydroxyl radicals by bioreductively activated antitumor quinones can in principle be uncoupled from alkylating activity.
Lusthof
K J
KJ
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, Sorbonnelaan, The Netherlands.
de Mol
N J
NJ
Richter
W
W
Janssen
L H
LH
Butler
J
J
Hoey
B M
BM
Verboom
W
W
Reinhoudt
D N
DN
D000970:Antineoplastic Agents / Q000378:metabolism*; D001388:Aziridines / Q000378:metabolism*; D004249:DNA Damage; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000970:Antineoplastic Agents; D001388:Aziridines; D005609:Free Radicals; D006878:Hydroxides; D011809:Quinones; D017382:Reactive Oxygen Species; D013481:Superoxides; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase