Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
28941780
DOI
10.1016/j.tox.2017.09.012
PII: S0300-483X(17)30292-5
Knihovny.cz E-resources
- Keywords
- Bis-dioxopiperazine, Cardioprotection, JR-311, Structure-activity relationship, Topoisomerase,
- MeSH
- Anthracyclines toxicity MeSH
- Iron Chelating Agents pharmacology MeSH
- Daunorubicin toxicity MeSH
- Dexrazoxane analogs & derivatives pharmacology MeSH
- Diketopiperazines pharmacology MeSH
- DNA Topoisomerases, Type II metabolism MeSH
- Myocytes, Cardiac drug effects MeSH
- Cardiotonic Agents pharmacology MeSH
- Cardiotoxicity drug therapy etiology MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Animals, Newborn MeSH
- Rats, Wistar MeSH
- Cell Proliferation drug effects MeSH
- Structure-Activity Relationship MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2,5-dioxopiperazine MeSH Browser
- Anthracyclines MeSH
- Iron Chelating Agents MeSH
- Daunorubicin MeSH
- Dexrazoxane MeSH
- Diketopiperazines MeSH
- DNA Topoisomerases, Type II MeSH
- JR-311 MeSH Browser
- Cardiotonic Agents MeSH
- Iron MeSH
Novel dexrazoxane derivative JR-311 was prepared to investigate structure-activity relationships and mechanism(s) of protection against anthracycline cardiotoxicity. Its cardioprotective, antiproliferative, iron (Fe) chelation and inhibitory and/or depletory activities on topoisomerase IIbeta (TOP2B) were examined and compared with dexrazoxane. While in standard assay, JR-311 failed in both cardioprotection and depletion of TOP2B, its repeated administration to cell culture media led to depletion of TOP2B and significant protection of isolated rat neonatal ventricular cardiomyocytes from daunorubicin-induced damage. This effect was explained by a focused analytical investigation that revealed rapid JR-311 decomposition, resulting in negligible intracellular concentrations of the parent compound but high exposure of cells to the decomposition products, including Fe-chelating JR-H2. Although chemical instability is an obstacle for the development of JR-311, this study identified a novel dexrazoxane analogue with preserved pharmacodynamic properties, contributed to the investigation of structure-activity relationships and suggested that the cardioprotection of bis-dioxopiperazines is likely attributed to TOP2B activity of the parent compound rather than Fe chelation of their hydrolytic metabolites/degradation products. Moreover, this study highlights the importance of early stability testing during future development of novel dexrazoxane analogues.
References provided by Crossref.org
Substituted Piperazines as Novel Potential Radioprotective Agents
Cardiac Troponins are Among Targets of Doxorubicin-Induced Cardiotoxicity in hiPCS-CMs
