ABSTRACT
The redox behaviour of the anti-cancer drug mitoxantrone was investigated in aprotic media (dimethylsulfoxide-DMSO) by coupled electrochemical and spectral EPR and UV/VIS absorption techniques. The cyclic voltammetry study with stationary and rotating disc electrode (RDE) of the reductive pathway of mitoxantrone points to two-electron transfers and evidences as intermediate species the anion radical, the dianion and the corresponding protonated species. EPR and optical spectra registered during the electrochemical reduction allow the identification of these species and suggest the possibility of back oxidation of the drug by electron transfer to molecular oxygen. The possibility of reductive activation of molecular oxygen by the intermediate species in the redox processes of mitoxantrone is discussed in connection with the cardiotoxicity of the drug. Gas phase and solvent-dependent AM1 and PM3 semiempirical MO calculations allow a rationalization of the experimental results regarding the reactivity in redox processes.
Subject(s)
Antineoplastic Agents/chemistry , Mitoxantrone/chemistry , Absorption , Dimethyl Sulfoxide/chemistry , Electrochemistry , Electrodes , Electron Spin Resonance Spectroscopy , Electrons , Oxidation-Reduction , Oxygen/chemistry , Spectrophotometry, UltravioletABSTRACT
The binding of the antitumoral drug actinomycin D to single- and double-stranded DNA was investigated using molecular modeling in the frame of MM+ molecular mechanics and AM1 semi-empirical method. Two other programs, especially conceived to analyze hydrogen-bonding patterns in biological macromolecules, HBexplore, based on geometrical criteria and SHB_interactions, based on quantum-chemical criteria (Mulliken overlap populations), were also used. The results account for the non-cooperative intercalative binding process previously investigated, and outline the contribution of specific hydrogen bonding as well as CH...O(N) and other atom-atom intermolecular interactions to the stabilization of the actinomycin D-DNA complexes. They also support the hemi-intercalation model proposed in literature for the actinomycin D-ssDNA complex.
