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
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Daunorubicin toxicity MeSH
- Diketopiperazines MeSH
- DNA Topoisomerases, Type II metabolism MeSH
- Topoisomerase II Inhibitors chemical synthesis metabolism therapeutic use MeSH
- Myocytes, Cardiac drug effects MeSH
- Cardiotonic Agents chemical synthesis metabolism therapeutic use MeSH
- Cardiotoxicity drug therapy MeSH
- Rats MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Animals, Newborn MeSH
- Piperazines chemical synthesis metabolism therapeutic use MeSH
- Rats, Wistar MeSH
- Cell Proliferation drug effects MeSH
- Saccharomyces cerevisiae Proteins metabolism MeSH
- Saccharomyces cerevisiae chemistry MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione MeSH Browser
- Daunorubicin MeSH
- Diketopiperazines MeSH
- DNA Topoisomerases, Type II MeSH
- Topoisomerase II Inhibitors MeSH
- Cardiotonic Agents MeSH
- Piperazines MeSH
- Saccharomyces cerevisiae Proteins MeSH
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.
References provided by Crossref.org
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