Buss J L, Hasinoff B B
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Arch Biochem Biophys. 1995 Feb 20;317(1):121-7. doi: 10.1006/abbi.1995.1143.
The ferrous- and ferric-ion-promoted hydrolysis of the doxorubicin cardioprotective agent dexrazoxane (ICRF-187) has been studied spectrophotometrically and by HPLC. While dexrazoxane itself did not undergo any iron-promoted ring-opening hydrolysis, both ferrous (t1/2 0.4 min) and ferric (t1/2 170 min) ions promoted, by factors of up to 6000 and 8, respectively, the hydrolysis of the one-ring open intermediates of dexrazoxane to yield the strongly metal-ion-chelating form. The pH dependence of both the ferrous- and ferric-ion-promoted hydrolysis of one of the one-ring open intermediates was studied and was consistent with base-catalyzed hydrolysis. In each case, due to the problem of proton ambiguity in the rate law, a bimolecular reaction with external hydroxide could not be distinguished from an intramolecular reaction of hydroxide bound to iron. The mechanism of the cardioprotective effects of dexrazoxane may involve enzymatic or nonenzymatic hydrolysis to the one-ring open intermediates. Thus, these intermediates may be the active forms of the drug that may be acting by either displacing iron from the iron-doxorubicin complex or chelating loosely bound iron and then undergoing a rapid metal-ion-promoted hydrolysis to their strongly chelating forms. Thus, the ability of iron to participate in site-specific hydroxyl radical damage may be reduced.
已通过分光光度法和高效液相色谱法研究了亚铁离子和铁离子促进的阿霉素心脏保护剂右丙亚胺（ICRF-187）的水解。虽然右丙亚胺本身并未发生任何铁促进的开环水解，但亚铁离子（半衰期0.4分钟）和铁离子（半衰期170分钟）分别以高达6000倍和8倍的系数促进右丙亚胺的单环开环中间体水解，生成强金属离子螯合形式。研究了亚铁离子和铁离子促进的其中一种单环开环中间体水解的pH依赖性，其与碱催化水解一致。在每种情况下，由于速率定律中质子模糊性的问题，与外部氢氧根的双分子反应无法与与铁结合的氢氧根的分子内反应区分开来。右丙亚胺心脏保护作用的机制可能涉及酶促或非酶促水解为单环开环中间体。因此，这些中间体可能是药物的活性形式，其作用方式可能是从铁-阿霉素复合物中置换铁，或螯合松散结合的铁，然后快速发生金属离子促进的水解，转化为其强螯合形式。因此，铁参与位点特异性羟基自由基损伤的能力可能会降低。
