title: Studies on DNA damage and induction of SOS repair by novel multifunctional bioreducible compounds. II. A metronidazole adduct of a ruthenium-arene compound.
abstract: A new transition metal complex of the 5-nitroimidazole, metronidazole (1-beta-hydroxyethyl-2-methyl-5-nitroimidazole), has been prepared and its potential use as a hypoxic cell cytotoxic agent examined. The preparation of the complex [(eta6-C6H6)RuCl2(metronidazole)] is described together with its characterization using standard spectroscopic techniques. Electrochemical investigations showed that coordination to the metal centre had not altered the electron affinity of the metronidazole, but kinetic studies using the cyclic voltametric mode demonstrated that the one-electron addition product, the nitro radical anion, had a decreased lifetime, with a half-life of 7.75 and 11.9 s for the coordinated and free metronidazole ligand respectively. Biological studies employed viscosity measurements, DNA SOS repair capacity and a transfection assay to examine the effect on DNA. Conductance studies were also employed to determine the influence on intact Escherichia coli growth rates. The ruthenium-metronidazole complex showed greater activity than metronidazole aerobically, but a higher differential activity under hypoxic reduction conditions, due to activation of the NO2 group. Results with intact cells suggested a greater selective cytotoxicity with metronidazole coordinated to ruthenium than attained with the free ligand.
authors.affiliation: Chemotherapy Research Unit, Polytechnic of East London, UK.
authors.forename: L D
authors.initials: LD
authors.lastname: Dale
authors.forename: J H
authors.initials: JH
authors.lastname: Tocher
authors.forename: T M
authors.initials: TM
authors.lastname: Dyson
authors.forename: D I
authors.initials: DI
authors.lastname: Edwards
authors.forename: D A
authors.initials: DA
authors.lastname: Tocher
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000633:toxicity; D004249:DNA Damage; D015195:Drug Design; D004563:Electrochemistry; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D008795:Metronidazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000633:toxicity; D013014:SOS Response, Genetics / Q000187:drug effects*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D008795:Metronidazole; C073422:Ru-metro