Evaluation of Thymidine, Dideoxythymidine and Fluorine Substituted Deoxyribonucleoside Geometry by the MIND0/3 Technique The Effect of Fluorine Substitution on Nucleoside Geometry and Biological Activity

Abstract

The MINDO/3 technique was used to evaluate the geometry of thymidine and four structural analogs, 3′-fluoro-3′-deoxythymidine (Z), 3′-fluoro-2′, T-dideoxy-P-D-lyxofuranosylthymine (3), 3′-deoxythymidine (4), and 3′,3′-difluoro-3′-deoxythymidine (5). The relative proportion of N (3′-endo, 2′-exo, P = 0°) and S (2′-endo, 3′-exo, P = 180°) conformers was determined for each of the analogs. Whereas the energy difference between the N and S forms of most deoxyribonucleoside derivatives differ by at most 1 to 2 kcal/mol, the N conformation for nucleosides 4 and 5 are respectively 2.9 and 4.0 kcal/mol more stable than the S form. The optimal value of χ for each of the analogs in the N conformation was -102° (4) and -97° (5). The fluorine in the up position at C3′ of deoxyribose appears to be a strong attractor for the H-6 proton on the thymine when the the sugar is in the N conformation.