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

  • J Med Chem. 2021 Apr 8;64(7):3997-4019. doi: 10.1021/acs.jmedchem.0c02157.
Anna Jirkovská  1 ,  Galina Karabanovich  1 ,  Jan Kubeš  1 ,  Veronika Skalická  1 ,  Iuliia Melnikova  1 ,  Jan Korábečný  2  3 ,  Tomáš Kučera  3 ,  Eduard Jirkovský  1 ,  Lucie Nováková  1 ,  Hana Bavlovič Piskáčková  1 ,  Josef Škoda  1 ,  Martin Štěrba  4 ,  Caroline A Austin  5 ,  Tomáš Šimůnek  1 ,  Jaroslav Roh  1
Affiliations
  • 1. Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
  • 2. Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Králové, Czech Republic.
  • 3. Faculty of Military Health Sciences, University of Defence, Třebešská 1575, 50005 Hradec Králové, Czech Republic.
  • 4. Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 50003 Hradec Králové, Czech Republic.
  • 5. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
PMID: 33750129 DOI: 10.1021/acs.jmedchem.0c02157
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.

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