Is “Frank” DNA‐Strand Breakage via the Guanine Radical Thermodynamically and Sterically Possible?

Using the reduction potential of one‐electron oxidized guanosine in water and the p K a values of the radical and of the parent, the N1−H bond energy of the 2′‐deoxyguanosine moiety is determined to be (94.3±0.5) kcal mol −1 . Using the DFT method, the energy of the N1‐centered guanosine radical is calculated and compared with those of the C1′‐ and C4′‐radicals formed by H‐abstraction from the 2′‐deoxyribose moiety of the molecule. The result is that these deoxyribose‐centered radicals appear to be more stable than the N1‐centered one by up to 3 kcal mol −1 . Therefore, H‐abstraction from a 2′‐deoxyribose C−H bond by an isolated guanosine radical should be thermodynamically feasible. However, if the stabilization of a guanine radical by intrastrand π–π interaction with adjacent guanines and the likely lowering of the oxidation potential of guanine by interstrand proton transfer to the complementary cytosine base are taken into account, there is no more thermodynamic driving force for H‐abstraction from a deoxyribose unit. As a further criterion for judging the probability of occurrence of such a reaction in DNA, the stereochemical situation that a DNA‐guanosine radical faces was investigated utilizing X‐ray data for relevant model oligonucleotides. The result is that the closest H‐atoms from the neighboring 2′‐deoxyribose units are at distances too large for efficient reaction. As a consequence, H‐abstraction from 2′‐deoxyribose by the DNA guanine radical leading subsequently to a “frank” DNA strand break is very unlikely. The competing reaction of the guanine radical cation with a water molecule which eventually yields 8‐oxo‐2′‐deoxyguanosine (leading to “alkali‐inducible” strand breaks) has thus a chance to proceed.