Interaction of topoisomerase II-targeted anticancer agents with the doxorubicin cardioprotective drug dexrazoxane, and synthesis of a dexrazoxane analog

Abstract

The anthrapyrazoles losoxantrone and piroxantrone are topoisomerase II-targeted anticancer agents that were developed as alternatives to anthracycline anticancer drugs, such as doxorubicin to prevent cardiotoxicity. In this study the formation of the Fe$\sp{3+}$ complexes of lo oxantrone and piroxantrone, and the dissociation of the complexes in the presence of dexrazoxane (ICRF-187, Zinecard$\sp\circler,$ Cardioxane$\sp\circler),$ and its hydrolyzed form ADR-925 were investigated spectrophotometrically. Both losoxantrone and piroxantrone were shown to chelate to Fe$\sp{3+}.$ These Fe$\sp{3+}$-drug complexes were shown to be dissociated in the presence of dexrazoxane and ADR-925. The Fe$\sp{3+}$-drug complex formation could be the cause of the observed cardiotoxic side effects induced by losoxantrone and piroxantrone in previous animal and clinical studies. The Fe$\sp{3+}$-drug dissociation could provide a way to minimize the cardiotoxicity when dexrazoxane and either losoxantrone or piroxantrone are used together. The antagonistic effects of dexrazoxane and topoisomerase II-targeted anticancer agents, such as m-amsacrine, etoposide, teniposide, losoxantrone, and piroxantrone were studied using Chinese hamster ovary cells. The above topoisomerase II-targeted anticancer agents were found to antagonize dexrazoxane at different concentrations. In order to improve the cardioprotective effect of dexrazoxane, an analog bisdioxopiperidine 1 was synthesized. The rate of the hydrolysis of compound 1 was found to be two times slower than that of dexrazoxane at 37$\sp\circ$C and pH 7.4. The hydrolyzed form of compound 1 was not a good Fe$\sp{3+}$ chelator compared to the hydrolyzed form of dexrazoxane, ADR-925.