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