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
posted on 2021-03-22, 20:30authored byAnna Jirkovská, Galina Karabanovich, Jan Kubeš, Veronika Skalická, Iuliia Melnikova, Jan Korábečný, Tomáš Kučera, Eduard Jirkovský, Lucie Nováková, Hana Bavlovič Piskáčková, Josef Škoda, Martin Štěrba, Caroline A. Austin, Tomáš Šimůnek, Jaroslav Roh
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.