COPPER(II) INTERACTIONS WITH AN EXPERIMENTAL ANTIVIRAL AGENT, 1-DEOXYNOJIRIMYCIN, AND OXYGEN ACTIVATION BY RESULTING COMPLEXES

1-deoxynojirimycin (DNJ), a 5-imino analog of 1-deoxyglucose, is a pot ent inhibitor of alpha-glucosidase I. DNJ and its derivatives have bee n considered as experimental drugs against human HIV-1 and hepatitis B viruses. Since amino and imino ligands have a high affinity for coppe r, it seems possible that biological activity of DNJ may be, at least in part, modulated by tissue copper. To test this possibility, potenti ometric and spectroscopic studies of the complexation of DNJ by cupric ions were performed in order to obtain thermodynamic and structural b ackground for further pharmacologic investigations. The effect of hist idine, a major tissue copper carrier, on coordination equilibria was a lso studied. Results indicate that DNJ and Cu(II) form two stable comp lexes at physiological pH, CuH-1(DNJ)(2)(+) and CuH-2(DNJ)(2), involvi ng 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 c omplexes are extremely effective mediators of in vitro oxidation of th e guanine moiety in both 2'-deoxyguanosine (dG) and DNA to 8-oxoguanin e (8-oxo-dG) and of DNA double strand scission by ambient O-2 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 cyt otoxic effects of systemically administered DNJ through oxidative dama ge mechanisms, and therefore the prospective use of DNJ for therapeuti c purposes must be developed with caution. On the other hand, however, the expected high genotoxic potential of synthetic Cu(II)-DNJ complex es may be used against viruses by means of targeted delivery of these complexes to the infected cells. (C) 1996 Elsevier Science Inc.