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 II? Interactions

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 inhibition and/or depletion topoisomerase II? (TOP2B) by could be cardioprotective. Hence, we evaluated a series analogues and found their cardioprotective strongly correlated with interaction TOP2B in cardiomyocytes, but was independent iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast rac-form 12, meso-derivative 11 (ICRF-193) showed favorable binding mode II silico, inhibited depleted cardiomyocytes more efficiently than dexrazoxane, highest efficiency. Importantly, observed ICRF-193 cardioprotection did not interfere antiproliferative anthracycline. this study identifies as new lead compound development efficient agents.