Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity

Abstract

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.

Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity in a rabbit modelin vivo

“…While the pharmacokinetics of GK-667 in rabbits has been reported previously [20], it remained unknown whether the pharmacokinetics of DAU and its main metabolite daunorubicinol (DAUol) are altered by GK-667 administration.…”

“…Fig. 1C) were synthesized and characterized in-house as described previously [11,20]. GK-667 and GK-627 were used as tetraand dihydro-chloride salts, respectively.…”

“…The most up-to-date-version is available at https://doi.org/10.1042/CS20210311 (n=10) dose, 30 min before each DAU dose to the contralateral ear. Doses and intravenous route of administration of GK-667 were set based on the previous pharmacokinetic study [20] and pilot experiments probing tolerability and efficacy of its combination with DAU. The timing of administration with respect to DAU was adopted from recommendations for clinical use of DEX [22] and previous experiments with DEX in our rabbit model [11,23].…”

“…Fig. 1A) as a new candidate for in vivo investigations [20]. GK-667 showed rapid release of active ICRF-193 both in vitro (in cell culture media and rabbit plasma) and in vivo (in rabbits).…”

“…Incubation of isolated neonatal cardiomyocytes with GK-667 induced significant intracellular concentrations of active ICRF-193 and showed high cytoprotective potency against ANT toxicity in this in vitro bioassay. Furthermore, the in vitro toxicity of GK-667 itself was low, and its administration to rabbits resulted in promisingly high plasma concentrations in vivo [20]. However, the translatability of these findings to complex in vivo conditions of chronic experiments was still unclear.…”