A Nuclear Magnetic Resonance Study of Nucleoside Conformation in Solution. The Effect of Structure and Conformation on the Magnetic Nonequivalence of the 5′-Methylene Hydrogens

Hruska, Frank E.; Wood, Donald J.; McCaig, T. N.; Smith, Adam; Holý, Antonı́n

doi:10.1139/v74-079

Cited by 46 publications

(11 citation statements)

References 31 publications

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“…3). Such couplings are consistent with an equilibrium between the gauche-gauche (y = 60') and the gauche-trans (y = 180') rotamers about C-4'-C-5' (17). Further evidence of such an equilibrium is obtained from NOE measurements after irradiation of H-5' or H-5".…”

Section: Arabinocytidine Derivative Ar3supporting

confidence: 71%

Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5′-hydroxyls for the syntheses of novel potential anticancer agents

Whitfield¹,

Douglas²,

Tang³

et al. 1994

Can. J. Chem.

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Contrary to expectations, many primary hydroxy groups are completely unreactive in glycosylation reactions, or give the desired glycosides in very low yields accompanied by products of many side reactions. Hydrogens of such primary hydroxyls are shown to be intramolecularly hydrogen bonded. Intermediates formed by nucleophilic attack by these hydroxyls on activated glycosylating agents may resist hydrogen abstraction. This resistance to proton loss is postulated to be the origin of the observed unreactivity. It is shown that successful glycosylations take place under acidic conditions under which such hydrogen bonds cease to exist. Accordingly, direct galactosylations of the normally unreactive 5'-hydroxyls of nucleosides were accomplished for the first time with a galactose trichloroacetimidate donor in chloroform under silver triflate promotion. It is noted that such galactosylated anticancer nucleosides may have improved biological specificity. Contrairement a ce que l'on peut privoir, plusieurs groupes hydroxyles primaires ne rtagissent pas du tout au cours des reactions de glycosylation ou avec seulement de faibles rendements accompagnCs de plusieurs sous-produits. On a dCmontrC que les hydrogknes de ces hydroxyles primaires sont impliquks dans des liaisons hydrogbnes. Les intermkdiaires qui se forment par attaque nuclCophile de ces hydroxyles sur des agents activCs de glycosylation peuvent rCsister a la reaction d'enlkvement de l'hydrogkne. ~e t t e r~sistance B la perte d'un proton se produit en milieu acide alors que de telles liaisons hydrogbnes cessent d'exister. On a rCalisC pour la premikre fois des galactosylations directes des hydroxyles normalement non rCactifs en 5' des nuclCosides en utilisant comme donneur un trichloroacCtimidate de galactose dans le chloroforme sous promotion par le triflate d'argent. I1 a CtC suggCrC que de tels nuclCosides anticanckreux galactosyles pourraient avoir une spCcificitC biologique amClioree.[Traduit par la redaction]

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Section: Arabinocytidine Derivative Ar3supporting

confidence: 71%

Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5′-hydroxyls for the syntheses of novel potential anticancer agents

Whitfield¹,

Douglas²,

Tang³

et al. 1994

Can. J. Chem.

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“…This suggests an almost identical influence of 4'-CHzOH upon H-6 in at least eight compounds. (A PMR analysis of the 5'-methylene hydrogens in numerous nucleosides [39] yields essentially the same correlation.) In Table 5 are summarized A6 values for H-6, H-5 and methyl groups in the presence of all the C-4' substituents available.…”

Section: 4mentioning

confidence: 62%

Pyrimidine Nucleosides in Solution

Follmann¹,

Pfeil²,

Witzel³

1977

European Journal of Biochemistry

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Proton magnetic resonance (PMR) spectra of 45 nucleoside and nucleotide derivatives of uracil, thymine, cytosine, 5-methylcytosine, and other substituted pyrimidines in water or dimethyl sulfoxide solutions have been analysed in order to correlate structure variations with molecular conformations and to gain insight into the nature of intramolecular forces which are responsible for the 'rigidity' of the molecules. Irrespective of thc structure of pyrimidine base and the absolute chemical shift values (6) the C(6)-H and, to a lesser degree, the C(5)-H and C(5)-CH3 resonances are shifted downfield by very similar amounts ( A S ) in the regular nucleosides or in the presence of charged or polar C-4' substituents. In detail, the following conformation-determining effects are seen.1. Ribose vs 2-deoxyribose substitution of a pyrimidine makes little difference for the chemical environment of base hydrogens but an intact pentofuranose ring (4'-0) and the exocyclic 5'-OH group are essential for a nucleoside to assume a specific conformation.2. Profound shielding or deshielding of H-6 by exocyclic nitrate, halogen, hydroxyl, phosphate, and carboxylate substituents indicates preference for the anti and gauche,gauche conformation ranges in all compounds except in the case of C-6 substitution.3. Halogen atoms and the hydroxyl group ( A 6 = 0.30 -0.40 ppm) interact with pyrimidine bases by induced polarisation of the C(5)=C(6) double bond, phosphate anions ( A 6 % 0.50 ppm) interact by the electrostatic attraction mechanism previously described, and in nucleoside 5'-carboxylates ( A 6 > 0.90 ppm) a hydrogen bond between -COO-and H-6 is formed.4. The deshielding effects caused by a 5'-OH group and monoanionic 5'-phosphate are similar ( A 6 % 0.35 -0.45 ppm), supporting the view that intramolecular rigidity of nucleosides and the nucleotide unit is not fundamentally different.This systematic survey, together with our previous studies of adenosine derivatives, provides a rationale for why the majority of both pyrimidine and purine nucleosides and nucleotides in solution exhibit closely comparable conformations, which in turn explain the group specificity of certain key enzymes in nucleic acid metabolism.Enzymes which act upon nucleosides or nucleotides usually show stringent specificities with respect to the conformation of the heterocyclic base, furanose moiety, and exocyclic hydroxyl or phosphate group of their substrates. For example, modified ribonucleotides in which the base deviates from a regular anti position are poor substrates of ribonucleases [l], RNA polymerase [2], or ribonucleotide reductase (H. Follmann and W. Ludwig, unpublished). 'H and13C nuclear magnetic resonance spectra are excellent tools to study This paper is part 3 of a series entitled Forces Stabilizing the Conformation of Nucleosides in Solution.Abbreviations. PMR, proton magnetic resonance. The IUPAC-IUB abbreviations are used for nucleic acid constituents. these three-dimensional structures in solutions, and in recent years have provided description...

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“…The tendency of 2'-deoxynucleosides to adopt the C2'-endo conformation is a manifestation of the 3'-OH gauche effect, which overrides the anomeric effect. For example, 2'-deoxyadenosine exists predominantly in the C2'-endo conformation (66% C2'-endo at 291°K) in solution (27 (2'-OH gauche effect). This conformation also places the thymine base in a pseudoaxial orientation which maximizes the 1,4-interaction of glycosidic nitrogen with one of the 04' lone pairs (anomeric effect).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for the RNA binding selectivity of oligonucleotide analogues containing alkylsulfide internucleoside linkages and 2′-substituted 3′-deoxyribonucleosides

et al. 1995

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INTRODUCTIONIn this report we describe the synthesis of oligonucleotides containing sulfide-linked dinucleoside units, namely rT(2'OH)dT, rT(2'0Me)5dT, dT8rU(2'OMe) and dT(2o0Me)5rU(2oMe). We also describe the interactions of such oligomers with complementary DNA and RNA targets, and provide the structural basis for their remarkable RNA binding selectivity. In all cases, the Tm values of the SIP-chimera duplexes were lower than those of the corresponding unmodified duplexes. We attribute this to steric interactions between the 5' sulfur and the atoms of the nearby base/sugar residues. The 2'-substituents (i.e., 2'OH or 2'OMe) vicinal to the alkylsulfide internucleoside linkage significantly perturb the structure and stability of the duplexes formed with DNA, and more so than with RNA. The introduction of three rT(2'OH)sdTp ( ' (5,6).Our research in the antisense field has focused on oligonucleotide analogues in which some of the phosphodiester groups are replaced by the dialkyl sulfide linkage 3'-CH2-CH2-S-CH2-5' (7-11). This linkage is non-hydrolyzable, non-ionic, and its length approximates that of a phosphodiester linkage reasonably well. More recently, we focused attention on the preparation of rT(20OH)SdT, rT(2 OMe)SdT, dTsrU(2'OMe) and rT(2'OMe)SrU(2'OMe) dimer units as well as their 3'-O-phosphoramidite derivatives for incorporation into oligonucleotides (11,12 (55°C, 16 h). The ammonia solution was collected by centrifuging the Eppendorf tube and then run through a Sephadex NAP-10 column which was pre-washed with 15 ml deionized water. The first eluting fractions (1.5 ml) were lyophilized to dryness and the resulting oligomer was redissolved in 1 ml of water. Purity of each oligomer was confmed by PAGE (26% polyacrylamide-7 M urea) run at 4°C, at a current of 10 mA, for 6-8 h (9). Melting experimentsMelting curves were measured in 10 mM NaH2PO4/Na2HPO4, 1 M NaCl buffer (pH 7.0) and analyzed the same way as described in reference 9. Circular dichroismThe CD spectrum ofeach sample was measured on a Jasco 500-C spectropolarimeter with a Jasco DP-J800/300 data processor. The cell temperature was kept at 50C. The concentration of the oligonucleotides were -2.5 jM (each strand).

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A Nuclear Magnetic Resonance Study of Nucleoside Conformation in Solution. The Effect of Structure and Conformation on the Magnetic Nonequivalence of the 5′-Methylene Hydrogens

Cited by 46 publications

References 31 publications

Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5′-hydroxyls for the syntheses of novel potential anticancer agents

Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5′-hydroxyls for the syntheses of novel potential anticancer agents

Pyrimidine Nucleosides in Solution

Structural basis for the RNA binding selectivity of oligonucleotide analogues containing alkylsulfide internucleoside linkages and 2′-substituted 3′-deoxyribonucleosides

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