Comprehensive structural studies of 2',3'-difluorinated nucleosides: comparison of theory, solution, and solid state.
The conformations of three 2',3'-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that the two vicinal fluorine atoms play in the puckering preferences of the furanose ring. Two of the compounds examined contained fluorine atoms in either the arabino or xylo dispositions at C2' and C3' of a 2',3'-dideoxyuridine system. The third compound also incorporated fluorine atoms in the xylo configuration on the furanose ring but was substituted with a 6-azauracil base in place of uracil. A battery of NMR experiments in D 2O solution was used to identify conformational preferences primarily from coupling constant and NOE data. Both (1)H and (19)F NMR data were used to ascertain the preferred sugar pucker of the furanose ring through the use of the program PSEUROT. Compound-dependent parameters used in the PSEUROT calculations were newly derived from complete sets of conformations calculated from high-level ab initio methods. The solution and theoretical data were compared to the conformations of each molecule in the solid state. It was shown that both gauche and antiperiplanar effects may be operative to maintain a pseudodiaxial arrangement of the C2' and C3' vicinal fluorine atoms. These data, along with previously reported data by us and others concerning monofluorinated nucleoside conformations, were used to propose a model of how fluorine influences different aspects of nucleoside conformations.
Laboratory of Medicinal Chemistry, National Cancer Institute, Frederick, National Institutes of Health, 376 Boyles Street, P.O. Box B, Frederick, Maryland 21702, USA. barchi@helix.nih.gov
Joseph J
JJ
Barchi
Rajeshri G
RG
Karki
Marc C
MC
Nicklaus
Maqbool A
MA
Siddiqui
Clifford
C
George
Igor A
IA
Mikhailopulo
Victor E
VE
Marquez
D018360:Crystallography, X-Ray; D003857:Deoxyuridine / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry; D005583:Fourier Analysis; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011741:Pyrimidine Nucleosides / Q000737:chemistry; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry
D006845:Hydrocarbons, Fluorinated; D011741:Pyrimidine Nucleosides; D005461:Fluorine; D014498:Uracil; C100248:azauracil; D003857:Deoxyuridine; D014529:Uridine