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
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- daunomycin toxicita MeSH
- diketopiperaziny MeSH
- DNA-topoisomerasy typu II metabolismus MeSH
- inhibitory topoisomerasy II chemická syntéza metabolismus terapeutické užití MeSH
- kardiomyocyty účinky léků MeSH
- kardiotonika chemická syntéza metabolismus terapeutické užití MeSH
- kardiotoxicita farmakoterapie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- novorozená zvířata MeSH
- piperaziny chemická syntéza metabolismus terapeutické užití MeSH
- potkani Wistar MeSH
- proliferace buněk účinky léků MeSH
- Saccharomyces cerevisiae - proteiny metabolismus MeSH
- Saccharomyces cerevisiae chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione MeSH Prohlížeč
- daunomycin MeSH
- diketopiperaziny MeSH
- DNA-topoisomerasy typu II MeSH
- inhibitory topoisomerasy II MeSH
- kardiotonika MeSH
- piperaziny MeSH
- Saccharomyces cerevisiae - proteiny MeSH
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.
Citace poskytuje Crossref.org
MicroRNAs in doxorubicin-induced cardiotoxicity: The DNA damage response
