Substituting CF₂for O4′ in Components of Nucleic Acids: Towards Systems with Reduced Propensity to Form Abasic Lesions

Abstract Intrinsic structural features and energetics of nucleotides containing variously fluorinated sugars as potential building blocks of DNA duplexes and quadruplexes are explored systematically using the modern methods of density functional theory (DFT) and quantum chemical topology (QCT). Our results suggest that fluorination at the 2′‐β or 2′‐α,β positions somewhat stabilizes in vacuo the AI relative to the BI conformations. In contrast, substitution of the CF 2 group for the O4′ atom (O4′‐CF 2 modification) leads to a preference of the BI relative to AI DNA‐like conformers. All the studied modifications result in a noticeable increase in the stability of the glycosidic bond [estimated by the relaxed force constants (RFC) approach], with particularly encouraging results for the O4′‐CF 2 derivative. Consequently, the O4′‐CF 2 modified systems are suggested and explored as promising scaffolds for the development of duplex and quadruplex structures with reduced propensity to form abasic lesions and to undergo DNA damage.