CONFORMATIONAL-ANALYSIS OF 2',3'-DIDEHYDRO-2',3'-DIDEOXYPYRIMIDINE NUCLEOSIDES

The molecular conformations of 2',3'-didehydro-2',3'-dideoxypyrimidine nucleosides have been studied by X-ray crystallographic analysis and molecular mechanics calculations. In this paper, the crystal structure s of the uridine, cytidine, and 5-ethyluridine analogues are reported. The structures of two crystal forms of the thymidine analogue and ano ther crystal form of the cytidine analogue that were reported elsewher e (Gurskaya et al. Int. J. Purine Pyrimidine Res. 1991, 2, 55-60. Hart e et al. Biochem. Biophys. Res. Commun. 1991, 175, 298-304. Birnbaum e t al. Nucleosides Nucleotides 1989, 8, 1259-1269.) are included in the analysis. In total twelve independent observations of the molecular c onformations of the unsaturated nucleosides are available because all six crystal forms have two molecules in the asymmetric unit. All molec ules have the dihydrofuran ring in a nearly planar conformation with a slight tendency toward O4'-endo. The glycosylic link is observed in t he unusual high-anti conformation in five of the twelve molecules. All but one of the 5'-hydroxyl groups are observed in the +sc conformatio n. The conformations are compared with those of their 2',3'-dideoxy an d 3'-substituted-2',3'-dideoxypyrimidine analogues. Least-squares fitt ing of the central four atoms (N1, C1', C2', and O4') of representativ e molecules of the three groups shows two distinct features of the fur anose ring conformations of the saturated compounds relative to those of the unsaturated analogues: the exocyclic deviation at C5' is smalle r for the common C3'-exo/C2'-endo or C3'-endo/C2'-exo conformations th an for the extreme C3'-exo/C4'-endo conformations observed frequently for the saturated and 3'-substituted analogues that have high anti-HIV activity. The opposite is observed for the endocyclic deviation at C3 '. The molecular mechanics calculations, consisting of gamma,chi-maps for the saturated and unsaturated thymidine analogues, confirm that th e high-anti glycosylic link conformation is more accessible and that o verall more area of conformational space is available for the unsatura ted than for the saturated compound. This can be explained by the redu ced ring puckering and the absence of out-of-plane hydrogen atom subst ituents at C2' and C3'. This increased flexibility of the molecule may make it more amenable for phosphorylation by making the ''active site ' conformation more accessible.