Carcinogenic Alkylation of Nucleic Acid Bases. Structure and Conformation of O4-Ethyl-2'-deoxythymidine in the Solid State and in Solution

Article abstract of DOI:10.1021/ja00267a042

O⁴-Ethyl-2'-deoxythymidine (e⁴dT) crystallizes in the monoclinic space group P2₁, and the cell dimensions are a = 5.079(1) Angstroem, b = 15.054(1) Angstroem, c = 8.467(1) Angstroem, β = 94.07(1) deg.X-ray intensity data were measured with a diffractometer, and the structure was solved by direct methods.Least-squares refinement, which included all hydrogen atoms; converged at R = 0.030 for 1365 observed reflections.The O-ethyl group is coplanar with the pyrimidine ring, the methylene carbon atom being syn to N3.It is shown that O⁴-alkylation causes significant changes in the geometry of the ring which can be attributed to an altered electronic structure.The conformation about the glycosidic bond is anti with χ_CN = 22.8 deg.The deoxyribose ring dopts the unusual C3' endo/C2' exo twist pucker, and the gauche(1+) rotamer of the CH2OH side chain is stabilized by an intramolecular C6-H...O5' hydrogen bond.Proton NMR data for e⁴dT and e⁴dU reveal the usual preference for the C2' endo sugar pucker and a conformer distribution for the C4'-C5' bond which is expected for 2'-deoxyribosides.Comments are made on the relevance of the structure to base mispairing of O-alkyl pyrimidines and their enzymatic repair.