1. 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
- Author
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Eduard Jirkovský, Jan Korábečný, Tomáš Šimůnek, Anna Jirkovská, Veronika Skalická, Hana Bavlovič Piskáčková, Martin Štěrba, Jan Kubes, Iuliia Melnikova, Jaroslav Roh, Tomas Kucera, Caroline A. Austin, Josef Skoda, Lucie Nováková, and Galina Karabanovich
- Subjects
Cardiotonic Agents ,Saccharomyces cerevisiae Proteins ,Anthracycline ,Diketopiperazines ,Saccharomyces cerevisiae ,Molecular Dynamics Simulation ,Pharmacology ,01 natural sciences ,Piperazines ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,ICRF 193 ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Topoisomerase II Inhibitors ,Structure–activity relationship ,Myocytes, Cardiac ,Cardioprotective Agent ,Rats, Wistar ,Cell Proliferation ,030304 developmental biology ,Cardioprotection ,0303 health sciences ,Cardiotoxicity ,Molecular Structure ,biology ,Topoisomerase ,Daunorubicin ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,DNA Topoisomerases, Type II ,Animals, Newborn ,chemistry ,biology.protein ,Molecular Medicine ,Dexrazoxane ,Protein Binding ,medicine.drug - 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 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.
- Published
- 2021