Myers C E, Muindi J R, Zweier J, Sinha B K
J Biol Chem. 1987 Aug 25;262(24):11571-7.
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.
5-亚氨基柔红霉素在pH 7.4时与Fe(III)形成3:1的复合物。药物-金属复合物的形成伴随着548和593 nm处吸光度的显著下降以及625 nm以上宽带的出现。5-亚氨基柔红霉素-Fe(III)复合物与过氧化氢反应产生·OH自由基。该反应在药物/铁比例为2:1时达到最大值，且产率远低于阿霉素-铁复合物。与阿霉素的结果相反，在高5-亚氨基柔红霉素/铁比例下，·OH的产生显著下降。羟基自由基的形成与5-亚氨基柔红霉素复合物切割超螺旋SV40 DNA的能力之间存在密切的平行关系。在高5-亚氨基柔红霉素:铁比例下，·OH和DNA损伤的抑制是多种因素的结果。1) DNA的存在刺激阿霉素复合物产生·OH，但不刺激5-亚氨基柔红霉素；2) 阿霉素将其螯合的Fe(III)还原为Fe(II)，但5-亚氨基柔红霉素不还原；3) 5-亚氨基柔红霉素形成如此稳定的药物-金属复合物，以至于溶剂水以及因此可能的H2O2难以接近螯合的铁。5-亚氨基柔红霉素的亲和力使其能够从阿霉素中定量提取铁。因此，5-亚氨基柔红霉素是阿霉素-铁复合物形成·OH自由基的有效竞争性抑制剂。
