Copper(II) interactions with an experimental antiviral agent, I-deoxynojirimycin, and oxygen activation by resulting complexes.
1-deoxynojirimycin (DNJ), a 5-imino analog of 1-deoxyglucose, is a potent inhibitor of alpha-glucosidase 1. DNJ and its derivatives have been considered as experimental drugs against human HIV-1 and hepatitis B viruses. Since amino and imino ligands have a high affinity for copper, it seems possible that biological activity of DNJ may be, at least in part, modulated by tissue copper. To test this possibility, potentiometric and spectroscopic studies of the complexation of DNJ by cupric ions were performed in order to obtain thermodynamic and structural background for further pharmacologic investigations. The effect of histidine, a major tissue copper carrier, on coordination equilibria was also studied. Results indicate that DNJ and Cu(II) form two stable complexes at physiological pH, CuH-1(DNJ)2+ and CuH-2(DNJ)2, involving Cu(II) chelation by the N-5 and O-6 donor atoms. In the presence of histidine, ternary complexes are also formed, of which the CuDNJHis+ species is stable in the physiological pH range. Binary Cu(II)-DNJ complexes are extremely effective mediators of in vitro oxidation of the guanine moiety in both 2'-deoxyguanosine (dG) and DNA to 8-oxoguanine (8-oxo-dG) and of DNA double strand scission by ambient O2 or H2O2. This mediation is suppressed by histidine in dG, but not in DNA. The results suggest that tissue Cu(II) may greatly enhance nonspecific cytotoxic effects of systemically administered DNJ through oxidative damage mechanisms, and therefore the prospective use of DNJ for therapeutic purposes must be developed with caution. On the other hand, however, the expected high genotoxic potential of synthetic Cu(II)-DNJ complexes may be used against viruses by means of targeted delivery of these complexes to the infected cells.
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland, USA.
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Jezowska-Bojczuk
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Kasprzak
D017485:1-Deoxynojirimycin / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D004249:DNA Damage; D004347:Drug Interactions; D004355:Drug Stability; D006639:Histidine / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010710:Phosphates / Q000737:chemistry; D011199:Potentiometry; D013057:Spectrum Analysis / Q000379:methods
D000998:Antiviral Agents; D010710:Phosphates; D017485:1-Deoxynojirimycin; D006639:Histidine; D003300:Copper