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Lookup NU author(s): Professor Caroline AustinORCiD
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.
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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