J. Poznanski et al., H-1 NMR conformational study of antiherpetic C5-substituted 2 '-deoxyuridines: Insight into the nature of structure-activity relationships, BIOC BIOP R, 272(1), 2000, pp. 64-74
Citations number
48
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
H-1 NMR study and conformational analysis of a broad series of biologically
important CB-substituted 2'-deoxyuridines, including alkyl, halogen, vinyl
, hydroxymethyl, and hydroxy derivatives as well as nitro, formyl, trifluor
omethyl, and dimethylamino substituents, is presented. A thorough analysis
of chemical shifts in correlation with CB-substituent electronegativity as
well as calculations by SCF semi-empirical method of the formal charge loca
lized on C6 carbon is discussed in terms of charge distribution for electro
n attracting and electron donating groups. Conformation of the sugar ring i
s determined from proton-proton coupling constants and described in terms o
f pseudorotation between two main puckering domains C2'endo (S) and C3'endo
(N). Generally, electron donating groups destabilise the N conformation, s
imultaneously decreasing the mean pseudorotation amplitude. Absolute assign
ments of the H5' and H5" methylene protons in H-1 NMR spectra permitted the
unequivocal determination of molar fractions of the three classical exocyc
lic C4'-C5' rotamers gauche(+), trans, and gauche(-), and correlation of th
em with the sugar ring puckering domains. Conformation about the glycosidic
bond is described in terms of equilibrium between two conformational regio
ns, anti and syn. Finally, the role of the CB-substituent in the creation o
f cytotoxic activity is considered on the basis of a simplified model assum
ing that compound activity is a function of substituent polar surface, its
molecular volume, and its molecule polarity defined at the relative partiti
on of the polar atoms. (C) 2000 Academic Press.