Bisdioxopiperazine agent
dexrazoxane (ICRF-187) has been the only effective and approved
drug for prevention of chronic
anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that
dexrazoxane derivatives exert cardioprotection via
metal chelation and/or modulation of topoisomerase IIβ (Top2B) activity in chronic
anthracycline cardiotoxicity.
Dexrazoxane was alkylated in positions that should not interfere with the
metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine
imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of
dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(±)-4,4'-(
propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic
anthracycline cardiotoxicity. In contrast to
dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and
metal-chelating properties of their metabolites were comparable to those of
dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against
anthracycline cardiotoxicity. SIGNIFICANCE STATEMENT: This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of
dexrazoxane, which is the only
drug approved for the prevention of
cardiomyopathy and
heart failure induced by
anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of
metal-chelating mechanisms for the induction of this effect and support the viability of topoisomerase IIβ as an upstream druggable target for effective and clinically translatable cardioprotection.