Nucleoside Reactions Shed Light on the Chemical Processes Underlying Interstrand Cross‐Link Formation at Apurinic/Apyrimidinic Sites in Duplex DNA

Abstract Apurinic/apyrimidinic (AP) sites in DNA can give rise to interstrand cross‐links via reactions of the ring‐opened AP‐aldehyde residue with the exocyclic amino groups of 2′‐deoxyadenosine, 2′‐deoxyguanosine, and 2′‐deoxycytosine residues (dA, dG, and dC) on the opposing strand to give imine/ N ‐glycosylamine linkages. Endogenous AP‐derived cross‐links in cellular DNA could contribute to cancer, aging, and neurodegeneration. The yields of AP‐derived cross‐links produced by the various nucleobases vary widely, and, until now, it remained unclear whether these differences might simply reflect differences in the inherent reactivities of the nucleobases. To shed light on this question, we examined reactions of a nucleosidic AP model compound, 3,5‐bis‐ O ‐methyl‐2‐deoxy‐D‐ribofuranose ( 1 ), with the canonical nucleosides (dA, dG, and dC) and the noncanonical nucleoside, 2‐aminopurine‐2′‐deoxyriboside (2AP). The trends observed for the equilibrium yields of the nucleoside cross‐links did not mirror yields of the respective cross‐links observed in the context of duplex DNA. The results provide evidence that the inherent reactivity of the nucleobases alone does not determine yields of AP‐derived cross‐links in duplex DNA. Rather, the differences in yields for the various AP‐derived cross‐links must reflect effects exerted by the 3D structure of double helical DNA on the cross‐linking processes.