Substituting CF2 for O4′ in Components of Nucleic Acids: Towards Systems with Reduced Propensity to Form Abasic Lesions

• Published in: Chemistry : a European journal Vol. 21; no. 49; pp. 17933 - 17943
• Main Authors: Yurenko, Yevgen P., Novotný, Jan, Sklenář, Vladimir, Marek, Radek
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.12.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Chemistry; density functional calculations; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA Damage; fluorinated compounds; G-Quadruplexes; Glycosides - chemistry; Molecular Structure; Nucleic Acid Conformation; Nucleic Acids - chemistry; Nucleotides - chemistry; relaxed force constants; density functional calculations; G-quadruplexes; fluorinated compounds; relaxed force constants; DNA
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201502977

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 CF2 group for the O4′ atom (O4′‐CF2 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′‐CF2 derivative. Consequently, the O4′‐CF2 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. Increasing resistance to DNA/RNA damage: Intrinsic conformational properties of ribose‐fluorinated nucleotides are described. On the basis of quantum chemical calculations, O4′‐CF2 modification is identified as a promising building block for nucleic acid duplexes and quadruplexes with a stronger glycosidic bond.