Using density functional theory to design DNA base analogues with low oxidation potentials

The oxidizability of substituted nucleobases was evaluated through theoreti cal calculations and the ability of individual bases to induce current enha ncement in the cyclic voltammograms of metal complexes. Formation of the gu anine derivatives 7-deazaguanine and 8-oxoguanine is known to lower the ene rgy for oxidation of guanine. The similar derivatives of adenine were exami ned and gave lower predicted redox energies as well as current enhancement with Ru(bpy)(3)(2+) (7-deazaadenine) and Fe(bpy)(3)(2+) (8-oxoadenine). Oxi dizable, substituted pyrimidines were identified using a computational libr ary that gave 5-aminocytosine and 5-aminouracil as promising electron donor s. Again, these predictions were verified using catalytic electrochemistry. In addition, the computations predicted that 6-aminocytosine would be redo x-active but not as easily oxidized as 5-aminocytosine, which was also conf irmed experimentally. In addition to calculating the relative one-electron redox potentials, we used calculations to evaluate the loss of a proton tha t occurs from the initially formed radical cation. These calculations gave results consistent with the experiments, and in the case of 8-oxoadenine, t he relative redox reactivity could be predicted only when the proton loss s tep was considered. These substituted bases constitute building blocks for highly redox-active nucleic acids, and the associated theoretical model pro vides powerful predictability for designing new redox-active nucleobases.