A novel intramolecular hydrogen bond in the crystal structure of 5-hydroxymethyl-2'-deoxyuridine, an antiviral and antineoplastic nucleoside. Conformational analysis of the deoxyribose ring

Abstract

The three-dimensional structure of 5-hydroxymethyl-2'-deoxyuridine, an inhibitor of herpes simplex and vaccinia viruses, was determined by X-ray crystallography. The crystals belong to the monoclinic space group P21, and the cell dimensions are u = 9.301 ( I ) , b = 12.302 ( I ) , c = 4.862 ( I ) A, 0 = 97.18 (I)'. Intensity data were measured with a diffractometer, and the structure was solved by direct methods; least-squares refinement converged at R = 0.050. In the -CH20H substituent at C(5), the hydroxy group occupies two different positions. The conformation about the glycosyl bond is anti (XCN = 56.4'), while the -CH20H side chain attached to the sugar ring adopts the gauche-gauche conformation. The deoxyribose ring has the relatively rare C( 1') exo pucker, possibly stabilized by a previously unobserved intramolecular hydrogen bond C(6)-H-O(4'). IH NMR spectroscopy was used to determine the conformation in solution. The spectra indicate an anti conformation about the glycosyl bond and a 43% contribution of the gauche-gauche conformation in the -CHzOH side chain. The sugar ring may exist in a 32:68 equilibrium of ' E and 2E conformers. However, the conventional interpretation may be inadequate since better agreement with observed coupling constants is obtained by assuming equal contributions of 3E, ! E , and 2E conformers.A survey of 5-substituted 2'-deoxyuridines reveals no correlation between the electronegativity of the substituents and either bond lengths or antiviral properties of these substances. (hmsdU)3 inhibits the replication of Escherichia coli 1 5T-,4 the reproduction of Ehrlich ascites carcinoma cellsS as well as a number of other mammalian cells,6 and the propagation of vaccinia and herpes simplex v i r~s e s .~ Early studies on the synthesis and metabolism of S h ydroxymethylpyrimidines and their derivatives have been reviewed by Ulbricht.8 Baker et aL9 prepared hmSdU by basecatalyzed hydroxymethylation of 2'-deoxyuridine, and, recently, hm5dU has been synthesized by Langen and Barwolff5 by selective monobromination of the 5-methyl carbon of thymidine under ultraviolet catalysis. 5-Hydroxymethylpyrimidine 2'-deoxyribonucleotides have also been prepared enzymically.I0 5-Hydroxymethyl-2'-deoxyuridylate competitively inhibits both prokaryotic and eukaryotic thymidylate synthetase' and has been found in the DNA of several Bacillus subtilis phages in place of thymidine.Is 5-Hydroxymethyl-2'-deoxyuridineSanti and SakaiI2 suggested that the inhibitory effect depends not only on the 5 substituent being of a size that avoids steric hindrance, but also on its electron-withdrawing property. More recently, Egert et a1.I6 attempted to demonstrate the influence of 5 substitution on the bond lengths in several uridine derivatives. An X-ray analysis of hmsdU, yielding both steric and electronic information about the -CH20H substituent at C(5), was expected to contribute to our understanding of the effects of such substituents. Furthermore, bearing in mind that its conformation must be related to its biologi...

2',3'-Didehydro-2',3'-dideoxy-5-hydroxymethyluridine

“…The distance between the N(1) base and the C(5') exocyclic substituent is 4.13 (3) A, which is in agreement with the value expected for their equatorial orientation (Saenger, 1984). The pyrimidine ring is not completely planar; the atoms with the largest deviations from the mean plane are C (4) [C(6)--H(6).-.O(4')] has been reported for 5-hydroxymethyl-2'-deoxyuridine (Birnbaum, Deslauriers, Lin, Shiau & Prusoff, 1980). In D4HMUrd the corresponding distances are C(6)...O(4') 2.94 (3) and H(6)...O(4') 2.76 A, which are not considered to be significantly different from the sum of the van der Waals radii of the contributing atoms.…”

Structure and conformation of the anticodon nucleoside 5-methoxyuridine in the solid state and in solution

“…higher precision and, in extension of our recent studies (4,(6)(7)(8)(9): to compare its conformation in the solid state with the solution conformation. as determined by an 'H and I3C nmr study.…”

Different Activities of 5-Hydroxy-dUMP and 5-Hydroxymethyl-dUMP in Thymidylate Synthase-Catalyzed Reaction in View of Molecular Modeling and Structural Studies

“…The data representing all variables were sampled from the Gaussian population. The number of observations was not very high (9), but the data were collected under fully reproducible experimental conditions to reduce nonsystematic errors. The multiple regression analysis was performed using GraphPad InStat version 3.01 for Windows FIG.…”

“…Structures tending to promote dissociation of the proton from the hydroxylic group are shown in bold (6,(9)(10)(11)(12).…”