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.

• 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