The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.

• MeSH
• Anthracyclines adverse effects   MeSH
• Dexrazoxane chemistry   pharmacology   MeSH
• Diketopiperazines chemistry   pharmacology   MeSH
• DNA Topoisomerases, Type II metabolism   MeSH
• Topoisomerase II Inhibitors chemistry   pharmacology   MeSH
• Myocytes, Cardiac drug effects   metabolism   MeSH
• Cardiotonic Agents chemistry   pharmacology   MeSH
• Cardiotoxicity drug therapy   metabolism   MeSH
• Rabbits MeSH
• Piperazine chemistry   pharmacology   MeSH
• Prodrugs chemistry   pharmacology   MeSH
• Razoxane chemistry   pharmacology   MeSH
• Water chemistry   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Male 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
• Anthracyclines MeSH
• Dexrazoxane MeSH
• Diketopiperazines MeSH
• DNA Topoisomerases, Type II MeSH
• Topoisomerase II Inhibitors MeSH
• Cardiotonic Agents MeSH
• Piperazine MeSH
• Prodrugs MeSH
• Razoxane MeSH
• Water MeSH