H-1 NMR conformational study of a variety of alpha-anomers of C5-substituted 2 '-deoxyuridines: Comparison to their antiherpetic beta counterparts

Although alpha -nucleosides are not found in nucleic acid, they do occur as constituents of smaller molecules in living cells, e.g., in vitamin B-12. There are now several examples of alpha -nucleosides exerting a biological activity in some instances equal to, or even exceeding, that of the corresp onding beta -anomer, Examples include growth inhibitory properties against mouse leukemia cells and antitumor activity. From stereochemical point of v iew, cu-anomers serve as references for studying of interaction of the base with the sugar moiety in beta -anomers and may help in better understandin g of structure-activity relationships. One important problem preventing con formational analysis of alpha nucleosides is uncertainty in the determinati on of vicinal coupling constants from simulation of overlapping sugar proto n resonances of strongly coupled spin systems. A successful resolution of n ear-isochronous H3' and H4' resonances made possible a full conformational analysis for a series of alpha -anomers C5-substituted 2'-deoxyuridines, in cluding methyl, ethyl, isopropyl, fluor, vinyl, and bromovinyl, in comparis on to their beta counterparts. Conformation of the sugar ring is determined from proton-proton coupling constants and described in terms of pseudorota tion between two main puckering domains C2' endo (S) and C3' endo (N). A th orough analysis of chemical shifts as well as conformation of the sugar rin g and C4'-C5' rotamers made possible determination of conformational prefer ences in equilibrium about the glycosidic bond between two regions, anti an d syn. This work provides insights into the role of anomeric configuration of the base in conformational behavior of the sugar moiety, a link in the b ackbone of nucleic acids. (C) 2001 Academic Press.