Electrochemistry Study of Antineoplastic Raltitrexed Oxidation Mechanism and its Interaction with DNA

Abstract

AbstractRaltitrexede (RTX) is a folate analogue that belongs to the antimetabolites family and has antineoplastic activity correlated to inhibition of the thymidylate synthase (TS) enzyme. This study addresses the electrochemical characterization of RTX at a glassy carbon electrode, on a wide interval of pH, using voltammetric techniques. The interaction between RTX and double helix DNA (dsDNA) in physiological medium is also addressed, using a DNA‐electrochemical biosensor. A mechanism for the electrochemical oxidation of RTX is proposed. RTX is irreversibly electroxidized under a predominantly diffusion controlled and pH‐dependent process. The oxidation process in acid and physiological media occurs in two consecutive steps. The first oxidation step is pH‐independent and associated with the transfer of one electron of the nitro group at N10 position by releasing a methyl cation. The second oxidation step is pH‐dependent and occurs with the transfer of one electron and one proton from the carbon at C9 position, followed by a direct attack by a water molecule leading to an irreversible dissociation of an oxidation product of RTX. A strong interaction between RTX and dsDNA was revealed by using a multilayer dsDNA electrochemical biosensor. The experiments demonstrated that RTX interacts and binds to the dsDNA helix by different interaction modes, suggesting an intercalation in between the DNA base pairs leading to defects in its secondary structure.