A 1H NMR Study of the Syn-Anti Dynamic Equilibrium in Adenine Nucleosides and Nucleotides with the Aid of Some Synthetic Model Analogues with Fixed Conformations (original) (raw)
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Journal of …, 1990
C A quantum chemical study of 10 substrates of adenosine deaminase is performed. The conformational preference around the glycosidic bond of several 8-substituted derivatives of adenosine is studied using semiempirical modified neglect of diatomic overlap (MNDO) and Austin model 1 (AM1) methods. All the compounds studied show preference for the anti conformation; the synanti energetic differences calculated are small and in excellent agreement with experimental data. A relationship between the ab initio molecular electrostatic potential minimum energy of N 3 and the synanti energetic difference is found. A highly significant relationship is also found between the ab initio net charge over the purine and pyrimidine rings and the logarithm of the maximum rate of deamination (log V, ) of the nucleosides by adenosine deaminase. In contrast, no significant relationship is found between the anti preference of 8-substituted derivatives of adenosine and their log V, of deamination.
Journal of Pharmaceutical Sciences, 1990
A quantum chemical study of 10 substrates of adenosine deaminase is performed. The conformational preference around the glycosidic bond of several 8-substituted derivatives of adenosine is studied using semiempirical modified neglect of diatomic overlap (MNDO) and Austin model 1 (AM1) methods. All the compounds studied show preference for the anti conformation; the syn – anti energetic differences calculated are small and in excellent agreement with experimental data. A relationship between the ab initio molecular electrostatic potential minimum energy of N3 and the syn – anti energetic difference is found. A highly significant relationship is also found between the ab initio net charge over the purine and pyrimidine rings and the logarithm of the maximum rate of deamination (log Vm) of the nucleosides by adenosine deaminase. In contrast, no significant relationship is found between the anti preference of 8-substituted derivatives of adenosine and their log Vm of deamination.
Biochimica et biophysica acta, 1977
The physical properties of an adenosine derivative, N(6)-dimethyl-2',3'-O-isopropylidene adenosine, Derivative 1, which is capable of intramolecular hydrogen bond formation between base-ring and sugar exocyclic hydroxymethyl group, have been studied in solution by infrared, circular dichroic and nuclear magnetic resonance spectroscopy. Analysis of the 220 MHZ 1H NMR spectrum of Derivative 1 in C2HCl2 solution indicated an overwhelming preference for the gg conformation for rotation about the C(4')--C5') bond and a predominant conformation for rotation about the C(5')--O(5') bond in which OH(5') projects towards the base ring. The purine base ring was shown to be in a predominant syn conformation with respect to the sugar ring by 100 MHZ 1H nuclear Overhauser experiments, by analysis of 3J(13C,H1') magnitudes observed in proton-coupled 13C NMR experiments and by CD measurements. Combination of each conformation feature of Derivative 1 in non-polar solv...
Journal of the American …, 1990
The conformational flexibility of adenosine in the gas phase is examined by molecular mechanic procedures. Results show that adenosine is found mainly in anti conformation (OI'Cl'N9C4 dihedral angle around 200-210°); a less stable conformation appears in the syn zone (glycosidic torsion angle around 50-60O). Two stable puckerings of the ribose are in the N and S areas, the S puckerings being more stable in both the anti and syn zones. The energy barriers for the anti-syn conversion are -4-5 kcal/mol, whereas the energy barriers for the pseudorotational movement S-N of the ribose are -2 kcal/mol through the east zone. Bidimensional studies have permitted us to determine three 'preferred" conformational areas for adenosine (S anti, N anti, and S syn), as well as the existence of "forbidden" conformational areas for this molecule (E high syn and high anti). Molecular modeling studies, where up to 69000 conformations were generated and tested, have permitted us to propose a set of active conformations of adenosine at the active site of adenosine deaminase, which are consistent not only with energy data shown in this paper, but also with substrate specificity obtained experimentally and reported in the literature. ( I ) Stolarski, R.; Hagberg, C.; Shugar, D. Eur. J . Eiochem. 1984, 138, (2) Altona. C.; Sundaralingam, M. J . Am. Chem. SOC. 1973. 95, 187-192. (5) Morange, M.; Kolb, A.; Buc, H.; Chachaty, C.; Langlet, G. Eur. J . 55-63. Eiochem. 1977. 74. 99-106. (6) Chachati, C'; Forchioni, A.; Morange, M.; BUC, H. Eur.
Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 1980
A study has been made by means of ~H-NMR spectroscopy of the syn .~ anti dynamic equilibrium about the glycosidic bond for 5'-deoxyadenosine and some 8-substituted analogues, in different solvents. The results are compared with those previously obtained for the parent adenosine and its 8-substituted analogues. Quantum chemical calculations, with the aid of the Classical Potential and PCILO procedures, were applied to obtain the energies for different conformations of the base in adenosine and 5'-deoxyadenosine, and their 8methyl and 8-halogeno derivatives. Good agreement was found between experimentally determined conformations in solution and those corresponding theoretically to the energy minima, particularly those calculated by the PCILO method. Comparison of the quantitative experimental data with the theoretical results was used to evaluate the validity of the latter and their applicability to studies of nucleoside conformation.
Journal of Medicinal Chemistry, 2002
1′-C-Methyl analogues of adenosine and selective adenosine A 1 receptor agonists, such as N-[(1R)-1-methyl-2-phenylethyl]adenosine ((R)-PIA) and N 6 -cyclopentyladenosine, were synthesized to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A 1 and A 2A receptors in rat brain membranes and at A 3 in rat testis membranes were determined and compared. It was found that the 1′-C-methyl modification in adenosine resulted in a decrease of affinity, particularly at A 1 and A 2A receptors. When this modification was combined with N 6 substitutions with groups that induce high potency and selectivity at A 1 receptors, the high affinity was in part restored and the selectivity was increased. The most potent compound proved to be the 1′-C-methyl analogue of (R)-PIA with a K i of 23 nM for the displacement of [ 3 H]CHA binding from rat brain A 1 receptors and a >435-fold selectivity over A 2A receptors. In functional assays, these compounds inhibited forskolin-stimulated adenylate cyclase with IC 50 values ranging from 0.065 to 3.4 µM, acting as full agonists. Conformational analysis based on vicinal proton-proton J-coupling constants and molecular mechanics calculations using the MM2 force field proved that the methyl group on C1′ in adenosine has a pronounced impact on the furanose conformation by driving its conformational equilibrium toward the north, γ+, syn form.
Acta Crystallographica Section B Structural Science, 2006
Over the last few years many efforts have been devoted to the discovery of new adenosine antagonists which can selectively bind to one of the four adenosine receptors, called A1, A2A, A2B and A3, in order to develop new drugs with few side effects. The present paper reports the crystal structures of four newly synthesized antagonists belonging to the chemical class of pyrazolo-triazolo-pyrimidine derivatives, which display good affinity and selectivity properties towards the A2A or A3 receptor subtypes. These molecules assume an overall planar conformation due to the formation of strong intramolecular N—H...N hydrogen bonds. A systematic investigation on molecules containing the ureidic —NH—C(=O,S)—NH—C=N— fragment has shown that the formation of such interactions is a common feature for this class of compounds. The associated energy, evaluated through DFT calculations, is some 50.24 kJ mol−1, leading to the conclusion that the hydrogen bond, and consequently the planar conformation...
NMR Studies on the syn-anti Dynamic Equilibrium in Purine Nucleosides and Nucleotides
European Journal of Biochemistry, 1980
The s.yn + anti equilibrium conformation about the glycosidic bond of purine nucleosides and 5'-nucleotides in different solvent systems has been investigated by means of 'H NMR spectroscopy. Quantitative values for the conformer populations were improved, relative to previous results, by a detailed study of, and a resultant derived correction for, the influence of the sugar exocyclic group conformation on the chemical shifts of the sugar ring protons. This was achieved with the aid of nucleosides and nucleotides fixed in the conformations gauche-trans [derivatives of 8,5'-(R)-cyclo] and trans-gauclze [derivatives of 8,5'-(S)-cyclo]. The results of 13C NMR confirmed those obtained by 'H NMR. The measured values of the vicinal coupling constants between H-1 ' and the C-8 and C-4 carbons were employed to evaluate approximately the glycosidic angles x of the nucleosides in the conformations s,yn and anti. A critical examination is made of the applicability of relaxation methods, involving analysis of spin-lattice relaxation time of protons ( T I ) and the Overhauser effect, to determine the conformation of the base about the glycosidic bond; interpretations are provided for the lack of agreement between these methods and those based on chemical shifts in the present study. The foregoing results are also applied to an examination of the effect of the conformation of the base about the glycosidic bond on the enzymatic reactions catalyzed by 5'-nucleotidase and adenosine deaminase.
Liebigs Annalen der Chemie, 1987
Anomalous coupliog at C-3 of unprotected 2-dcoxy-&ribose (2) with M'-acyladenosincs 1 was performed using P,Q,&lfl/Bu~N in chloroform as the coupling reagant. The 3-(9-adenyl)-2,34deoxy-Brkreu-pentopyran0.w formed wcm deprotcctcd with ,ammonia in methanol to give the anomalously coupled isomer 5 of adenosine. The chemistry of 2-deoxy-~-ribose (2) and the synthesis of 2-deoxynucleosides has been a subject of great interest, not only because of the biological importance of this group of compounds, but also because of the challenging synthetic problems enco~ntered~?~). It was recently noted in our laboratory4) that various N6-aryl-substituted purines reacted with unprotected 2-deoxy-~-ribose (2) in the presence of a P4010/H20/Bu3N reagent to give anomalous coupling products of purines to C-3 of 2-deoxy-~-ribose (2,3-dideoxy-3-(9-purinyl)-~-pentoses). The main theme of this work is to investigate a simple approach for synthesis of the adenosine analogue 3-(9-adenyl)-2,3-dideoxy-~-threo-pentopyranose. For this purpose N6-aroyl-, N6-acyl-, and N6-furoyladenines were prepared according to known procedures5-') and subjected to coupling with unprotected 2-deoxy-~-ribose in P4010/H20/ Bu3N/CHC13 at 40°C for one week. Among eighteen N6-acyladenines 1 prepared in this investigation four amides (R = CH3, CH=CHC6Hs, 3,4-C12C6H3, and 4-O2NC6H4) turned out to be too insoluble in the chloroform reagent mixture and seven amides [R = C2H5, (CH2)3CH3, [CH2]4CH3, [ICH216CH,, C(CH313, CH2C6Hs and 4-CH30C6H4] could be coupled with 2 as recognized by TLC but without precipitation of the desired product 3. From other investigations we knew that silica chromatographic workup of the coupled products 3 would be rather tedious because of a large excess of phosphates present in the reaction mixture. Furthermore, the coupled products 3 were very unstable in the presence of phosphates. Aqueous workup resulted in cleavage of 3 and the starting material 1 was the only product isolated in spite of the fact that 3 later on was shown to be stable in water. Because of these difficulties we were therefore looking for appropriate acyl derivatives which allowed the coupled products 3 to u8gcrr6Micb wrknitpfte NarleasiQ. U1'!verkniipfung von ugc&kkr EDesoxy.s*lbose nn C-3 mh Nb-Acyhdadnen, ein newt Weg zn Isomom des Adctmias Die ungewiihnliche Ycrkniipfung von N'-Acyladenincn I mil C-? von unpchiitztcr 2-Desoxy-rrribose (2) gclingl mit P,O,$HJII Bu3N als Kuppluogsreagens in Chloroform. Von den so crhaltcncn 3.(9-A&nyl)-2,3-didcsoxy-~-ihrecr-pcntopyranoscn 3 wurden mit Ammoniak in Methanol die Acylgruppen unicr Bildunp dcs ungewehnlich wcrkniipftcn Isomers 5 von Adcnosin ahgcspaiten. '1 Part I1 J. Andersen, E. B. Pedersen, Liebigs Ann. Chem. 1987, 705. reduced pressure and the residue was suspended in afew ml of 96% ethanol. Filtration and subsequent recrystallization from water afforded pure 5.-EI M S m/z (%) = 251 (6, M'), 162 (29), 136 (31),
Biochimica Et Biophysica Acta (bba) - Nucleic Acids and Protein Synthesis, 1974
Circular dichroism spectra of uridine derivatives were measured in various solvents. Miles' diagram (Miles, D.W., Robins, M.J., Robins, R.K., Winkley, M.W. and Eyring, H. (1969) J. Am. Chem. Soc. 91,831--838) was qualitatively confL-med and the important role of the 5'-OH group in the stabilization of the syn conformer was established. An analysis of crystallographic data indicates that the furanose ring constrained by an additional dioxolane ring assumes the envelope conformation. For this type of sugar puckering the syn and anti conformations are energetically equal. The conformation of 3',5'-and 2',3'cyclophosphates is discussed in terms of the results obtained for model compounds. * NMRCAL (Nicolet Instrument Corp. 5225 Verona Road, Madison, Wisconsin).