- 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
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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.
- Jirkovská, Anna,Karabanovich, Galina,Kube?, Jan,Skalická, Veronika,Melnikova, Iuliia,Korábe?ny, Jan,Ku?era, Tomá?,Jirkovsky, Eduard,Nováková, Lucie,Bavlovi? Piská?ková, Hana,?koda, Josef,?těrba, Martin,Austin, Caroline A.,?im?nek, Tomá?,Roh, Jaroslav
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p. 3997 - 4019
(2021/05/04)
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- 1-ACRYLOYLIMIDAZOLIDINE-2-ONE COMPOUND
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To provide a compound that is expected to be applied to cell culture materials, temperature-responsive polymer materials and the like.SOLUTION: The present invention relates to a 1-acryloylimidazolidine-2-one compound represented by formula (1) (where R1a is a hydrogen atom, a C1 to 4 alkyl group, a benzyl group or an oxyalkyl group represented by formula (2). R2a is a hydrogen atom or a C1 to 4 alkyl group. R3a is a hydrogen atom or a methyl group).SELECTED DRAWING: None
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Paragraph 0059-0061
(2021/03/03)
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- Lipophilic polyamines useful for treating hypercholesterolemia
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This invention relates to novel lipophilic polyamines of formula I, the method of using these compounds to treat hypercholesterolemia, and intermediates thereto.
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