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

Abstract

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 disproportion-comproportionation 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.

In Situ Reactivity of Electrochemically Generated Nitro Radical Anion on Tinidazole and Its Monomeric and Dimeric CuII Complexes on Model Biological Targets with Relative Manifestation of Preventing Bacterial Biofilm Formation

“…The glassy carbon electrode maintained at a previously determined reduction potential of each compound helped to electrochemically generate different reduction products in aqueous solution that includes RNO 2 •– under de-aerated (Ar saturated) conditions. Because in the immediate vicinity of such in situ generated reduction products, thymine or cytosine or adenine or calf thymus DNA were maintained (separately), and they got an opportunity to interact with the species generated. ,, Time for in situ electrochemical generation of reduced species either on the monomeric or dimeric complexes or on tnz was strictly maintained constant for a certain target so that results obtained for nucleic acid bases and calf thymus DNA, due to each compound used could be compared with regard to species generated in solution. , The generated species bring about a change on the target maintained in the immediate vicinity of their generation. − Using the same experimental setup in aqueous solution, reduction of tnz was carried out at −0.745 V (pH 7.4), the monomeric complex at −0.700 V (pH 7.4), and the dimeric complex at −0.710 V (pH 7.4). The nucleic acid bases or calf thymus DNA were each investigated following interaction with reduced products formed either on tnz or on tnz present as a ligand in the complexes. ,, Concentrations of compounds used in the study were 1/10 that of the target (nucleic acid bases or calf thymus DNA).…”

“…26,27,53 Time for in situ electrochemical generation of reduced species either on the monomeric or dimeric complexes or on tnz was strictly maintained constant for a certain target so that results obtained for nucleic acid bases and calf thymus DNA, due to each compound used could be compared with regard to species generated in solution. 54,55 The generated species bring about a change on the target maintained in the immediate vicinity of their generation. 53−55 Using the same experimental setup in aqueous solution, reduction of tnz was carried out at −0.745 V (pH 7.4), the monomeric complex at −0.700 V (pH 7.4), and the dimeric complex at −0.710 V (pH 7.4).…”

Increased Free Radical Generation during the Interaction of a Quinone-Quinoline Chelator with Metal Ions and the Enhancing Effect of Light

“…For example, a decrease in DNA damage is observed in the case of alizarin and emodin complexes with Mn(II). In contrast, emodin complexes with Cu(II) are redox active and involved in the Fenton reaction, generating hydroxyl (•OH) radicals, which, in turn, enhance the modification of nucleobases [ 25 , 30 ].…”