Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

Cytotoxicity by anthracycline antibiotics is attributed to several pathways. Important among them are formation of free-radical intermediates. However, their generation makes anthracyclines cardiotoxic which is a concern on their use as anticancer agents. Hence, any change in redox behavior that address cardiotoxicity is welcome. Modulation of redox behavior raises the fear that cytotoxicity could be compromised. Regarding the generation of free radical intermediates on anthracyclines, a lot depends on the surrounding environment (oxic or anoxic), polarity and pH of the medium. In case of anthracyclines, one-electron reduction to semiquinone or two-electron reduction to quinone-dianion are crucial both for cytotoxicity and for cardiotoxic side effects. The disproportioncomproportionation equilibria at play between quinone-dianion, free quinone and semiquinone control biological activity. Whatever is the form of reduction, semiquinones are generated as a consequence of the presence of anthracyclines and these interact with a biological target. Alizarin, a simpler anthracycline analogue and its Mn-II complex were subjected to electrochemical reduction to realize what happens when anthracyclines are reduced by compounds present in cells as members of the electron transport chain. Glassy carbon electrode maintained at the pre-determined reduction potential of a compound was used for reduction of the compounds. Nucleobases and calf thymus DNA that were maintained in immediate vicinity of such radical generation were used as biological targets. Changes due to the generated species under aerated/de-aerated conditions on nucleobases and on DNA helps one to realize the process by which alizarin and its Mn-II complex might affect DNA. The study reveals alizarin was more effective on nucleobases than the complex in the free radical pathway. Difference in damage caused by alizarin and the Mn-II complex on DNA is comparatively less than that observed on nucleobases; the complex makes up for any inefficacy in the free radical pathway by its other attributes.

Automated summary

Cytotoxicity of anthracycline antibiotics is mainly attributed to the generation of free-radical intermediates, which may also lead to cardiotoxicity. Modulation of redox behavior needs to balance cytotoxicity and cardiotoxicity. Experimental results suggest that anthracycline analogues have a significant impact on nucleobases, while their effects on DNA are relatively minor.