5-Iminodaunomycin. An anthracycline with unique properties.
5-Iminodaunomycin forms a 3:1 complex with Fe(III) at pH 7.4. Drug-metal complex formation is associated with a marked decline in absorbance at 548 and 593 nm and the appearance of a broad band above 625 nm. The 5-iminodaunomycin-Fe(III) complex reacts with hydrogen peroxide to yield .OH radicals. This reaction is at a maximum at a drug/iron ratio of 2:1, and the yield is far less than that obtained with the doxorubicin-iron complex. In contrast to the results with doxorubicin, the production of .OH declines markedly at high 5-iminodaunomycin/iron ratios. There is a close parallel between the formation of hydroxyl radicals and the ability of the 5-iminodaunomycin complex to nick supercoiled SV40 DNA. The suppression of both .OH and DNA damage at high 5-iminodaunomycin:iron ratios is the result of several factors. 1) The presence of DNA stimulates .OH production from the doxorubicin complex, but not 5-iminodaunomycin; 2) doxorubicin reduces its chelated Fe(III) to Fe(II), but 5-iminodaunomycin does not; 3) 5-iminodaunomycin forms such a stable drug-metal complex that solvent water and, therefore, presumably H2O2, has diminished access to the chelated iron. The affinity of 5-iminodaunomycin is such that it can quantitatively abstract iron from doxorubicin. As a result, 5-iminodaunomycin is an effective competitive inhibitor of .OH radical formation by the doxorubicin-iron complex.
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003497:Cyclic N-Oxides; D004278:DNA, Superhelical / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000378:metabolism; D004317:Doxorubicin; D004578:Electron Spin Resonance Spectroscopy; D005290:Ferric Compounds; D006863:Hydrogen-Ion Concentration; D006878:Hydroxides; D017665:Hydroxyl Radical; D009603:Nitroso Compounds; D013539:Simian virus 40
D003497:Cyclic N-Oxides; D004278:DNA, Superhelical; D004279:DNA, Viral; D005290:Ferric Compounds; D006878:Hydroxides; D009603:Nitroso Compounds; D017665:Hydroxyl Radical; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D004317:Doxorubicin; C034526:tert-nitrosobutane; C018979:5-iminodaunorubicin; D003630:Daunorubicin