In situ electrochemical evaluation of dsDNA interaction with the anticancer drug danusertib nitrenium radical product using the DNA-electrochemical biosensor

摘要

Danusertib is a kinase inhibitor and anti-cancer drug. The evaluation of the interaction between danusertib and dsDNA was investigated in bulk solution and using the dsDNA-electrochemical biosensor. The dsDNA-danusertib interaction occurs in two sequential steps. First, danusertib binds electrostatically todsDNA phosphate backbone through the positively charged piperazine moiety. The second step involved the pyrrolo-pyrazolemoiety and led to small morphological modifications in the dsDNA double helix which were electrochemically characterised through the changes of guanine and adenine residue oxidation peaks and confirmed by electrophoretic and spectrophotometric measurements. The nitrenium cation radical product of danusertib amino group oxidation was electrochemically generated in situ on the dsDNA-electrochemical biosensor surface. The danusertib nitrenium cation radical redox Metabolite was covalently attached to the C8 of guanine residues preventing their oxidation. An interaction mechanism of dsDNA-danusertib is proposed and the formation of the danusertib redox nitrenium radical metabolite-guanine adduct explained. (C) 2015 Elsevier B.V. All rights reserved.