Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase II beta inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F21%3A10434484" target="_blank" >RIV/00216208:11150/21:10434484 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11160/21:10434484
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=_eqVDJ.Rf4" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=_eqVDJ.Rf4</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41598-021-83688-x" target="_blank" >10.1038/s41598-021-83688-x</a>
Alternative languages
Result language
angličtina
Original language name
Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase II beta inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
Original language description
The bisdioxopiperazine topoisomerase II beta 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Scientific Reports
ISSN
2045-2322
e-ISSN
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Volume of the periodical
11
Issue of the periodical within the volume
1
Country of publishing house
GB - UNITED KINGDOM
Number of pages
14
Pages from-to
4456
UT code for WoS article
000626810000003
EID of the result in the Scopus database
2-s2.0-85101584952