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

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 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase
II in silico, 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.

右雷佐生（dexrazoxane，ICRF-187）是目前唯一获批用于对抗蒽环类药物诱导心脏毒性的临床药物，其心脏保护活性传统上被归因于其铁螯合代谢产物。然而，近期实验证据表明，右雷佐生对拓扑异构酶IIβ（TOP2B）的抑制乃至耗竭作用，同样可能介导其心脏保护效应。为此，我们对一系列右雷佐生类似物开展了评估，结果显示其心脏保护活性与心肌细胞内TOP2B的结合作用显著相关，而与其铁螯合能力无关。针对4,4′-(丁烷-2,3-二基)双(哌嗪-2,6-二酮)的立体异构体，本研究验证了极强的构效关系：与其外消旋体12不同，内消旋衍生物11（ICRF-193）在计算机模拟实验（in silico）中展现出与拓扑异构酶II更优的结合模式，其对心肌细胞内TOP2B的抑制与耗竭效率均优于右雷佐生，且心脏保护活性最高。值得注意的是，ICRF-193所展现的心脏保护作用并未干扰蒽环类药物的抗增殖活性。因此，本研究确认ICRF-193可作为高效心脏保护剂开发的全新先导化合物。