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Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions

Lookup NU author(s): Emerita Professor Caroline AustinORCiD

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2021.

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Abstract

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.

Publication metadata

Author(s): Jirkovska A, Karabanovich G, Kubes J, Skalicka V, Melnikova I, Korabecny J, Kucera T, Jirkovsky E, Novakova L, Bavlovic Piskackova H, Skoda J, Sterba M, Austin CA, Simunek T, Roh J

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2021

Volume: 64

Issue: 7

Pages: 3997-4019

Print publication date: 08/04/2021

Online publication date: 22/03/2021

Acceptance date: 02/04/2018

Date deposited: 08/01/2022

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acs.jmedchem.0c02157

DOI: 10.1021/acs.jmedchem.0c02157

PubMed id: 33750129

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