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...

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Autores principales:	Hana Bavlovič Piskáčková, Hana Jansová, Jan Kubeš, Galina Karabanovich, Nela Váňová, Petra Kollárová-Brázdová, Iuliia Melnikova, Anna Jirkovská, Olga Lenčová-Popelová, Jaroslav Chládek, Jaroslav Roh, Tomáš Šimůnek, Martin Štěrba, Petra Štěrbová-Kovaříková
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5b4e58f79de6467488f64f6509b130b3
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spelling	oai:doaj.org-article:5b4e58f79de6467488f64f6509b130b32021-12-02T13:30:11ZDevelopment of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity10.1038/s41598-021-83688-x2045-2322https://doaj.org/article/5b4e58f79de6467488f64f6509b130b32021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83688-xhttps://doaj.org/toc/2045-2322Abstract 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.Hana Bavlovič PiskáčkováHana JansováJan KubešGalina KarabanovichNela VáňováPetra Kollárová-BrázdováIuliia MelnikovaAnna JirkovskáOlga Lenčová-PopelováJaroslav ChládekJaroslav RohTomáš ŠimůnekMartin ŠtěrbaPetra Štěrbová-KovaříkováNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hana Bavlovič Piskáčková Hana Jansová Jan Kubeš Galina Karabanovich Nela Váňová Petra Kollárová-Brázdová Iuliia Melnikova Anna Jirkovská Olga Lenčová-Popelová Jaroslav Chládek Jaroslav Roh Tomáš Šimůnek Martin Štěrba Petra Štěrbová-Kovaříková Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
description	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.
format	article
author	Hana Bavlovič Piskáčková Hana Jansová Jan Kubeš Galina Karabanovich Nela Váňová Petra Kollárová-Brázdová Iuliia Melnikova Anna Jirkovská Olga Lenčová-Popelová Jaroslav Chládek Jaroslav Roh Tomáš Šimůnek Martin Štěrba Petra Štěrbová-Kovaříková
author_facet	Hana Bavlovič Piskáčková Hana Jansová Jan Kubeš Galina Karabanovich Nela Váňová Petra Kollárová-Brázdová Iuliia Melnikova Anna Jirkovská Olga Lenčová-Popelová Jaroslav Chládek Jaroslav Roh Tomáš Šimůnek Martin Štěrba Petra Štěrbová-Kovaříková
author_sort	Hana Bavlovič Piskáčková
title	Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
title_short	Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
title_full	Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
title_fullStr	Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
title_full_unstemmed	Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
title_sort	development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase iiβ inhibitor icrf-193 as potential cardioprotective agents against anthracycline cardiotoxicity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5b4e58f79de6467488f64f6509b130b3
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Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity

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