THE ONE-RING OPEN HYDROLYSIS PRODUCT INTERMEDIATES OF THE CARDIOPROTECTIVE AGENT ICRF-187 (DEXRAZOXANE) DISPLACE IRON FROM IRON-ANTHRACYCLINE COMPLEXES
THE ONE-RING OPEN HYDROLYSIS PRODUCT INTERMEDIATES OF THE CARDIOPROTECTIVE AGENT ICRF-187 (DEXRAZOXANE) DISPLACE IRON FROM IRON-ANTHRACYCLINE COMPLEXES
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DOI：
10.1007/bf01976756
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发表时间：
1993-09-01
期刊：
影响因子：
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通讯作者：
HASINOFF, BB
中科院分区：
文献类型：
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作者：
BUSS, JL;HASINOFF, BB
研究了心脏保护剂ICRF-187（右雷佐生）、其单环开环水解产物和其双环开环水解产物ADR-925从其与阿霉素、柔红霉素、表阿霉素和伊达比星的络合物中置换Fe 3+的能力。在pH 7.4时，浓度为100 μ M的ICRF-187缓慢但完全地从其蒽环类配合物中置换Fe 3+，半衰期为230 - 450 min。时间范围从1.7到16.7分钟。分子建模的Fe 3+配合物与一个环开放的中间体表明，这些中间体可能作为四齿配体。由于这些中间体是如此好的螯合剂，它们也可能是预防氧自由基衍生的铁基蒽环类药物诱导的心脏毒性的活性物质。由于这些开环中间体是通过母体ICRF-187水解产生的，比ADR-925更快，因此形成生物活性物质的速度可能比以前认为的更快。双环开环水解产物ADR-925对蒽环类抗生素配合物中的Fe ~（3+）的置换也迅速而完全，半衰期为1 ~ 3 min。
The ability of the cardioprotective agent ICRF-187 (dexrazoxane), its one-ring open hydrolysis products, and its two-ring open hydrolysis product, ADR-925, to displace Fe3+ from its complex with doxorubicin, daunorubicin, epirubicin and idarubicin have been studied. At pH 7.4, ICRF-187 at a concentration of 100 muM ICRF-187 slowly but completely displaced Fe3+ from its anthracycline complexes with half-times ranging from 230 to 450 min. The one-ring open intermediate hydrolysis products were also shown to be chelating agents and were also able to displace quickly and completely Fe3+ from its anthracycline complexes with half-times ranging from 1.7 to 16.7 min. Molecular modeling of Fe3+ complexes with the one-ring open intermediates showed that these intermediates were likely acting as tetradentate ligands. Since these intermediates are such good chelating agents, they may also be pharmacologically active species in preventing oxygen-radical derived iron-based anthracycline-induced cardiotoxicity. Since these one-ring open intermediates are produced by hydrolysis from the parent ICRF-187 more quickly than is ADR-925, the formation of pharmacologically active species might be occurring more quickly than previously thought. The displacement of Fe3+ from its anthracycline complexes by the two-ring open hydrolysis product ADR-925 also took place quickly and completely with half-times ranging from 1 to 3 min.