Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
28941780
DOI
10.1016/j.tox.2017.09.012
PII: S0300-483X(17)30292-5
Knihovny.cz E-zdroje
- Klíčová slova
- Bis-dioxopiperazine, Cardioprotection, JR-311, Structure-activity relationship, Topoisomerase,
- MeSH
- antracykliny toxicita MeSH
- chelátory železa farmakologie MeSH
- daunomycin toxicita MeSH
- dexrazoxan analogy a deriváty farmakologie MeSH
- diketopiperaziny farmakologie MeSH
- DNA-topoisomerasy typu II metabolismus MeSH
- kardiomyocyty účinky léků MeSH
- kardiotonika farmakologie MeSH
- kardiotoxicita farmakoterapie etiologie MeSH
- krysa rodu Rattus MeSH
- kultivované buňky MeSH
- novorozená zvířata MeSH
- potkani Wistar MeSH
- proliferace buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 2,5-dioxopiperazine MeSH Prohlížeč
- antracykliny MeSH
- chelátory železa MeSH
- daunomycin MeSH
- dexrazoxan MeSH
- diketopiperaziny MeSH
- DNA-topoisomerasy typu II MeSH
- JR-311 MeSH Prohlížeč
- kardiotonika MeSH
- železo 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.
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