Comparative DNA damage induced by nitroimidazole-aziridine drugs: 1. Effects of methyl substitution on drug action.
RSU-1069 (1-(-3-aziridinyl-2-hydroxypropyl)-2-nitroimidazole) is a bifunctional chemo- and radiosensitizing agent. The properties of these functional groups may be examined by comparison of drug-induced DNA damage oxically, a measure of aziridine-induced damage and, during anoxic electrochemical reduction of the nitro-group, a measure of DNA damage resulting from the combined activity of reduced nitro group intermediates and alkylation by the aziridine moiety. In this study, a series of nitroimidazole aziridines have been studied and compared. The compounds used were RSU-1069, five methyl substituted derivatives: RSU-1131, RSU-1150, RSU-1164, RSU-1172, RB-7040; a 4-nitroimidazole derivative, RSU-1170, and RSU-1137, the non-alkylating hydrolysis product of RSU-1069. DNA damage, occurring oxically or as a consequence of nitro reduction, decreases with increasing substitution of the aziridine ring. Most DNA damage occurring oxically is produced by RSU-1069 and RSU-1170, both compounds having unsubstituted aziridine rings; least DNA damage is produced by RSU-1137. In general, the extent of DNA damage during electrochemical reduction is greater than that occurring oxically, this being due to an assumed combination of alkylation and reduced nitro-group intermediates. There is a direct correlation between the half-lives of the compounds and the extent of DNA damage occurring under oxic conditions. A direct correlation of the aerobic toxicities of the compounds tested, relative to RSU-1069, and the number of unsubstituted sites available for nucleophilic attack on the aziridine moiety has also been shown.
Dale
L D
LD
Chemotherapy Research Unit, North East London Polytechnic, London, UK.
Tocher
J H
JH
Edwards
D I
DI
D003090:Coliphages; D004249:DNA Damage; D004277:DNA, Single-Stranded; D004279:DNA, Viral; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000633:toxicity; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011048:Polarography; D013329:Structure-Activity Relationship
D004277:DNA, Single-Stranded; D004279:DNA, Viral; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole