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阿霉素心脏毒性双二氧哌嗪类化合物构效关系研究表明,ICRF-193 是拓扑异构酶 IIβ 相互作用最强的强效双二氧哌嗪类化合物。

Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions.

机构信息

Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic.

Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Králové, Czech Republic.

出版信息

J Med Chem. 2021 Apr 8;64(7):3997-4019. doi: 10.1021/acs.jmedchem.0c02157. Epub 2021 Mar 22.

Abstract

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form , meso-derivative (ICRF-193) showed a favorable binding mode to topoisomerase II , inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.

摘要

地拉佐辛(ICRF-187)是唯一被临床批准用于预防蒽环类药物引起的心脏毒性的药物,其具有心脏保护活性,传统上归因于其铁螯合代谢物。然而,最近的实验证据表明,地拉佐辛抑制和/或耗尽拓扑异构酶 IIβ(TOP2B)可能具有心脏保护作用。因此,我们评估了一系列地拉佐辛类似物,发现它们的心脏保护活性与其在心肌细胞中与 TOP2B 的相互作用强烈相关,但与它们的铁螯合能力无关。在 4,4'-(丁烷-2,3-二基)双(哌嗪-2,6-二酮)的立体异构体上证明了非常紧密的构效关系。与外消旋形式相比,内消旋衍生物(ICRF-193)与拓扑异构酶 II 具有有利的结合模式,在心肌细胞中比地拉佐辛更有效地抑制和耗尽 TOP2B,并显示出最高的心脏保护效率。重要的是,观察到的 ICRF-193 的心脏保护作用不会干扰蒽环类药物的抗增殖活性。因此,本研究确定 ICRF-193 为开发有效心脏保护剂的新先导化合物。

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