Proton magnetic resonance studies of 2'-deoxyadenosine (2'-dA), 3'-deoxyadenosine (3'-dA), 5'-deoxyadenosine (5'-dA) and 8-bromo-5'-deoxyadenosine (8-Br-5'-dA) have been carried out in the temperature range between -60 degrees and +40 degrees C for ND3 solutios, +40 degrees and +100 degrees C for D2O solutions, and finally +10 degrees and +60 degrees C for pyridine solutions. The analysis is based on the two-state S in equilibrium N model of the ribose moiety proposed by Altona and Sundaralingam. In all solvents, 2'-dA favours slightly the S state of the ribose and the g+ conformer of the exocyclic CH2OH group. However, 3'-dA prefers strongly the N state of the ribose and the g+ conformation. Both the S and N states of the ribose are equally favoured by 5'-DA and 8-Br-5'-dA. Evidence for the existence of an intramolecular hydrogen bond between 0(5') and N3 in purine (beta)-nucleosides is presented. It is also concluded that cordycepin (3'-dA) exists in solution mainly in the anti conformation of the base relative to the ribose.
The ribose conformations of 8-azaadenosine, 8-azaguanosine, and 8-azainosine have been studied using proton magnetic resonance in ND3 solutions, in D2O solutions, and in pyridine solutions. The temperature was varied between - 60 and + 40 ° C in ND3 and between + 10 and + 60 °C in D2O solutions. The analysis is based on the two state S ⇌ N model of the ribose moiety proposed by Altona and Sundaralingam. In D2O, the 8-aza substitution destabilizes the gg rotamer and simultaneously diminishes the population of the S state of the ribose. It is deduced that the anti population of the base is greater in the 8-azapurine (β) ribosides than in the common purine (β) -ribosides.
The solution conformation of adenosine(β)ribosides modified at the 2′, 3′ or 5′ position is derived from the analysis of the HRNMR spectra of the ribose protons. The conformational equilibria of the furanoside rings are described by the two state N ↔ S model introduced by Altona and Sundaralingam. The new compounds studied are: 2′-thiobenzoyl-2′-deoxyadenosine, 3′-thio-3′-deoxyadenosine, 2′-chloro-2′-deoxyadenosine, 3′-chloro-3′-deoxyadenosine, 2′-bromo- 2′-deoxyadenosine, 3′-bromo-3′-deoxyadenosine, 2′-O-methyladenosine, 3′-O-methyl-adenosine, 2,-deoxy-3,-O-methyladenosine, 5′-amino-5′-deoxyadenosine, 5′-acido-5′-deoxyadenosine, and 5′-chloro-5′-deoxyadenosine. The emphasis in this work is to study systematically the influence of the different substituents upon the conformational equilibria of the sugar. It is found that any substitution at the 2′ position stabilizes the S-conformer. An even more pronounced stabilization of the A-conformer in the 3′ substituted analogs is observed. The equilibrium changes in these classes of compounds can neither be correlated quantitatively with electronegativity differences nor with sterical differences between the various substituents. Substitution at the 5′ position influences the N ↔ S equilibrium only slightly, but has significant effects upon the conformational preferences of the exocyclic 5′-CH2R3 group.
The solution conformations of 9-β-ᴅ-arabinofuranosyladenine analogues modified at the 2′,3′ or 5′ positions are derived from the HRNMR spectra and the longitudinal relaxation rates of the protons. The compounds studied are: 9-β-ᴅ-arabinofuranosyladenine and its 2′-amino-2′-deoxy, 2′-chloro-2′-deoxy, 2′-azido-2/-deoxy, 3′-amino-3′-deoxy, 3′-bromo-3′-deoxy, 3′-chloro-3′- deoxy, 3′-fluoro-3′-deoxy, 3r-azido-3′-deoxy, 2,,3,-diamino-2′,3′-dideoxy, 2′,5′-diamino-2′,5′-di- deoxy and 2′,5′-diazido-2′,5′-dideoxy analogues. It is derived from the data that the conformational equilibria of the furanoside rings can be described by the two state N ⇔ 5 model of Altona and Sundaralingam. The emphasis in this work is to study systematically the influence of the different chemical modifications upon the conformational equilibria of the nucleosides. For the arabinosides it is found that substitution of the hydroxyl groups at C2′ or C3′ by other atoms or groups always stabilizes the N conformation oi the araoinose ring. The only exception is fluorine, where S is stabilized. The preference for the N state is correlated with an increasing population of the g+ rotamer of the exocyclic 5′-CH2OD group. From the relaxation study of 2′-chloro-2′-deoxy- arabinofuranosyladenine the position of the syn ⇔ anti equilibrium of the base was estimated to be predominantly anti. Thus a preference for the anti-N-g+ conformation was derived for the arabinosides excluding an intramolecular hydrogen bond between the 2′ and 5′ hydroxyl groups that was found in the solid state. The stabilization of the N conformer in the modified compounds can be qualitatively explained by steric effects.
Proton magnetic resonance studies of 9-β-ᴅ-xylofuranosyladenine (xyloA), its 2′-amino-2′- deoxy, 2′-azido-2′-deoxy, 2′-bromo-2′-deoxy, 3′-thio-3′-deoxy, 3′-amino-3′-deoxy, 3′-azido-3′- deoxy, 3′-chloro-3′-deoxy, 3′-fluoro-3′-deoxy, 3′-O-methyl, 3′,5′-diazido-3′,5′-dideoxy analogues and 9-β-ᴅ-lyxofuranosyladenine (lyxoA) have been carried out to study the effect of chemical modifications at the sugar moiety on the solution conformational equilibria in these classes of nucleosides. Analogously to previous studies the xylose pucker can be described in the two-state N ⇔ S model of Altona and Sundaralingam. For the xylosides, however, a somewhat different N state (C3′-endo-C4′-exo) has to be used than for the ribosides and arabinosides (C2′-exo-C3′- endo). The results of the conformational analysis are that xyloA exists almost exclusively as an N conformed The effect of the substitutions in the modified compounds is to destabilize the N state. This decrease in the mole fraction of N is accompanied by an increase in the population of the g+ rotamer of the exocylic 5′-CH2OD group. Thus for the xylosides a correlation N-t/g- or S- g+, respectively, can be derived. Proton relaxation rate measurements on 2′-azido-2′-deoxyxylo- furanosyladenine indicate that in the xylosides the standard syn or anti ranges do not represent stable positions for the adenine base, but that a glycosyl torsion angle (Χ∼160°, Υ∼80°) be tween syn and anti is preferred. LyxoA behaves similar to the xylosides and also favours the N state of the sugar pucker. In a summarizing discussion the conformational equilibria of the different modified pentosides - ribose, arabinose, xylose and lyxose - are compared. It is shown that generally intramolecular hydrogen bonding does not yield an important contribution to the stabilization of conformational equilibria in solution. It is also not possible to derive a quantitative relationship between such parameters as Van-der-Waals’ radii or electronegativity of the substituents and the mole fractions of the different conformers. It can, however, be seen that in all cases, where the hydroxyl groups at C2′ or C3′ are substituted by a more voluminous atom or group, steric effects become dominant and allow a qualitative explanation of the changes of the conformational equilibria. Only for the smallest and most electronegative substituents, like fluorine, other interactions (e.g. electrostatic) may become important. It is thus suggested that the purine(β)nucleoside conformation is essentially determined by steric interactions between the different parts of the molecule.
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