Structural studies of O6-methyldeoxyguanosine and related compounds: a promutagenic DNA lesion by methylating carcinogens.

O6-Methylation of guanine residues in DNA can induce mutations by formation of base mispairing due to the deprotonation of N(1). The electronic, geometric and conformational properties of three N(9)-Substituted O6-methylguanine derivatives, O6-methyldeoxyguanosine (O6mdGuo), O6-methylguanosine (O6mGuo) and O6, 9-dimethylguanine (O6mdGua), were investigated by X-ray and/or NMR studies. O6mdGuo crystallizes in the monoclinic space group P2(1) with cell parameters a = 5.267(1), b = 19.109(2), c = 12.330(2) A, beta = 92.45(1) degrees, V = 1239.8(3) A3, z = 4 (two nucleosides per asymmetric unit), and O6mGua in the monoclinic space group P2(1)/n with cell parameters a = 10.729(2), b = 7.640(1) c = 10.216(1) A, beta = 92.17(2) degrees, V = 836.7(2) A3, z = 4. The geometry and conformation of O6-methylguanine moieties observed in both crystals and are very similar. Furthermore, the molecular dimensions of the O6methylguanine residue resemble more closely those of adenine than those of guanine. The methoxy group is coplanar with the purine ring, the methyl group being cis to N(1). The conformation of O6-methylguanine nucleosides is variable. The glycosidic conformation of O6mdGuo is anti for molecule (a) and high-anti for molecule (b) in the crystal, while that of O6mGuo is syn [Parthasarathy, R & Fridey, S. M. (1986) Carcinogenesis 7, 221-227]. The sugar ring pucker of O6mdGuo is C(2')-endo for molecule (a) and C(1')-exo for molecule (b). The C(4')-C(5') exocyclic bond conformation in O6mdGuo is gauche- for molecule (a) but trans for molecule (b), in contrast with gauche+ for O6mGuo. The hydrogen bonds exhibited by O6-methylguanine derivatives differ from those in guanine derivatives; the amino N(2) and ring N(3) and N(7) atoms of O6-methylguanine residues are involved in hydrogen bonding. 1H-NMR data for O6mdGuo and O6mdGuo reveal the predominance of a C(2')-endo type sugar puckering. In O6mdGuo, however, a contribution of a C(1')-exo sugar puckering is significant. The NOE data also indicate that O6mdGuo molecules exist with nearly equal population for anti (including high anti) and syn glycosidic conformations. These observations and their biological implications are discussed.     

Molecular orbital studies on nucleoside analogs. II. Conformation of 6-azapyrimidine nucleosides.

PCILO (Perturbative Configuration Interaction using Localised Orbitals) computations have been carried out for three 6-azapyrimidine nucleosides, 6-azauridine, 6-azacytidine and 6-azathymidine, for both C(2')-endo and C(3')-endo pucker of the sugar ring. The results indicate a syn (chiCN=180 degrees) conformation followed by chiCN=90 degrees and gg conformation for C(3')-endo 6-aza analogs as compareed to the anti (chiCN=0 degrees) and gg conformation preferred by the corresponding pyrimidine nucleosides. For C(2')-endo sugar geometry, 6-azauridine and 6-azacytidine prefer, respectively, chiCN=0 degrees (anti) and phi C(4')-C(5')=60 degrees C (gg) and chiCN-240 degrees (syn) and phi C(4')-C(5')=120 degrees. The corresponding nucleosides, uridine and cytidine, show a preference for syn (chiCN=240 degrees) and gg and anti(chiCN=0 degrees) and gg , respectively. The X-ray crystallographic conformations of 6-azauridine and 6-azacytidine have been attributed to intermolecular hydrogen bonding and crystal packing forces. The results of PMR, CD and ORD studies on 6-azauridine and 6-azacytidine in aqueous solutions are in agreement with the PCILO predictions.     

A novel guanine-guanine base pairing: crystal structure of a complex between 7-methylguanosine and its iodide.

7-Methylguanosine, one of the biologically important minor nucleosides, could be crystallized as a complex of its zwitterionic form and its iodide, and the crystal structure was determined by the X-ray diffraction method. The crystals belong to the triclinic space group P1 with the unit cell dimensions: a = 7.678(1), b = 18.094(3), and c = 5.711(1) A, alpha = 79.32(1), beta = 80.14(1) and gamma = 76.90(1) degrees. The structure was solved by the heavy atom method and refined by the least-squares method to give a final R index of 0.075. The novel reverse Watson-Crick type base pairing observed between a positively charged molecule and a deprotonated one indicates that the deprotonation at the N(1) position promoted by the alkylation at the N(7) position may interrupt the formation of the normal Watson-Crick type GC base pair. The conformations about the glycosidic bond and the sugar puckering are quite different between the two molecules: the former has anti and C(4')-exo,C(3')-endo and the latter syn and C(1')-exo-C(2')-endo.     

Conformational analysis of arabinonucleosides and nucleotides. A comparison with the ribonucleosides and nucleotides.

Conformations of arabino nucleosides and nucleotides have been analyzed by semiempirical energy calculations. It is found that the change in the configuration of the O(2')-hydroxyl group in arabinoses compared to riboses exerts significant influence on the conformational priorities of the glycosyl and the exocyclic C(4')-C(5') bond torsions. While the anti conformations for the bases are preferred, the anti in equilibrium or formed from syn interconversion is considerably hampered compared to ribosides due to large energy barrier. Further the preferred anti glycosyl torsions are shifted to higher values for C(3')-endo puckers and in ribosides. While the gauche+ conformation around the C(4')-C(5') bond is favored for C(3')-endo arabinosides, it is strongly stabilized for C(2')-endo arabinosides only in the presence of the intrasugar hydrogen bond O(2')-H ... O(5'). The net attractive electrostatic interactions between the phosphate and the base stabilizes the preferred conformations of 5'-arabinonucleotides also.     

Molecular structures of two new anti-HIV nucleoside analogs: 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine and 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)hypoxanthine.

The x-ray crystal structures of two new anti-HIV compounds, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (2'-F-dd-araA) and 9-(2,3-dideoxy-2-fluoro-beta-D-threo- pentofuranosyl)hypoxanthine (2'-F-dd-aral), have been determined at two temperatures. Both crystals are in the space group P2(1)2(1)2(1), and their structures were solved by direct methods. Least-squares refinement produced final R-factors of 0.027 for the 2'-F-dd-araA structure and of 0.044 for the 2'-F-dd-aral structure, respectively. The latter structure contains a two-fold disordered conformation of the sugar moiety. All three conformers (one for 2'-F-dd-araA and two for 2'-F-dd-aral) adopt an anti chi CN glycosyl torsion angle. The sugar in the 2'-F-dd-araA structure has a C2'-endo pucker conformation, whereas the sugar in the 2'-F-dd-aral structure has a mixture of C2'-endo and C3'-endo pucker conformations. When the sugar adopts the C2'-endo conformation, the torsion angle about the C4'-C5' bond is in a transgauche+ conformation. In contrast, when the sugar adopts the C3'-endo conformation, the torsion angle about the C4'-C5' bond is in a gauche(+)-gauche- conformation. The C2'-F bond distance is 1.406(3) A, similar to that found in other aliphatic C-F bonds. The results suggest that the 2'-fluoro-2',3'-dideoxyarabinosyl nucleosides do not have a strong preference for either C2'-endo or C3'-endo sugar pucker.     

Molecular orbital studies on the structure of nucleoside analogs. I. Conformation of 8-azapurine nucleosides

PCILO (perturbative configuration interaction using localized orbitals) computations have been carried out for the conformational properties of 8-azapurine nucleosides. The results indicate an anti conformation for Xcn and a gg conformation for phiC(4')-C(5') for C(2')-endo 8-aza analogs compared to the syn and gg conformation for the corresponding purine nucleosides. For C(3')-endo sugar puckering, both molecules prefer the syn conformation due to intramolecular hydrogen bonding between O(5')-H of the sugar and N(3) of the base, the preference being more profound in 8-aza analogs. The crystallographic conformation 8-azaadenosine has been attributed to crystal forces. The available NMR data on 8-azapurine nucleosides are in agreement with the PCILO predictions.     

The crystal and molecular structure of 8-methyladenosine 3'-monophosphate dihydrate.

8-Methyladenosine 3'-monophosphate dihydrate was synthesized and crystallized in the monoclinic space group P21 with the unit cell dimensions: a = 9.095(2) A, b = 16.750(3) A, c = 5.405(2) A and beta = 97.61(3) degrees. The structure was determined by the application of the heavy atom method and refined to give a final R factor of 0.047. The pertinent conformations are as follows: the syn conformation about the glycosyl bond (chiCN = 216.8 degrees), the C(2')-endo sugar puckering with the displacement of 0.55 A; and the gauche-gauche conformation about the C(4')-C(5') bond capable of forming an intramolecular hydrogen bonding between N(3) of adenine base and O(5') of the hydroxymethylene group on the ribose. The molecule exists in the zwitterionic form with the N(1) of the adenine base protonated by a phosphate proton and is stabilized by three-dimensional networks of hydrogen bonding through the crystalline water molecules or directly between the adjacent nucleotide molecules; no base stacking was observed.     

Investigations on the dynamic structures of adenine- and thymine-containing DNA.

The structures of poly(dA-dT), poly(dA-dBr5U) and of poly(dA).poly(dT) have been investigated in solution and in fibers, by Raman spectroscopy. Both the alternating poly(dA-dT), poly(dA-dBr5U) and non-alternating poly(dA).poly(dT) exhibit, in the region of sugar phosphate backbone vibrations, two bands of almost equal intensity at about 841 cm-1 and 817 cm-1. The analysis of the characteristic bands of thymine residues that are sensitive to sugar puckers gives indication of a significant displacement from the C(2')-endo conformer suggesting the adoption of alternative conformers such as O(4')-endo. In contrast, the diagnostic Raman bands for the sugar pucker of adenine residues suggest, instead, predominant adoption of C(2')-endo conformations. These Raman results are compatible with rapid dynamic changes of sugar puckers between C(2')-endo and O(4')-endo for the thymidine (and uridine) residues, whereas in adenine residues the sugar puckers fluctuate around the C(2')-endo pucker in all synthetic DNA molecules studied. Molecular dynamics simulations, performed on six different starting models using two distance-dependent dielectric functions epsilon(r) = 4 r and a sigmoidal dependence), all gave similar dynamic behavior in agreement with these Raman data and their interpretation. The mean calculated pseudorotation phases of the adenine residues are systematically higher (around C(2')-endo) than those of the thymine residues (close to O(4')-endo-C(1')-exo). Besides, the mean lifetimes of the thymine residues are 1.5 to 2.0-fold higher in the O(4')-endo than in the C(2')-endo domain, while those of the adenine residues are two to threefold higher in the C(2')-endo than in the O(4')-endo domain. In the Raman spectra of the alternating poly(dA-dBr5U), the splitting of a band into two components arising from the two contributions of ApBr5U and Br5UpA provides strong evidence for a repeating dinucleotide structure in solution. The calculated twist values averaged over the simulation runs are also systematically higher in the 5'T-A3' step (39 degrees) than in the 5'A-T3' step (33 degrees). Simultaneously, the calculated roll values are positive in the 5'T-A3' step (6 degrees) and negative in the 5'A-T3' step (-9 degrees), while the propeller twist values are about the same (-11 degrees to -16 degrees). On the other hand, in the homopolymer, the average twist value is close to 36 degrees with the roll angle close to 0 degrees and large propeller twist values (-20 degrees).     

8-Chloroguanosine: solid-state and solution conformations and their biological implications

The three-dimensional structure of 8-chloroguanosine dihydrate was determined by X-ray crystallography. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), and the cell dimensions are a = 4.871 (1) A, b = 12.040 (1) A, and c = 24.506 (1) A. The structure was determined by direct methods, and least-squares refinement, which included all hydrogen atoms, converged at R = 0.031 for 1599 observed reflections. The conformation about the glycosidic bond is syn with chi CN = -131.1 degrees. The ribose ring has a C(2')-endo/C-(1')-exo (2T1) pucker, and the gauche+ conformation of the -CH2OH side chain is stabilized by an intramolecular O-(5')-H...N(3) hydrogen bond. Conformational analysis by means of 1H NMR spectroscopy showed that, in dimethyl sulfoxide, the sugar ring exhibits a marked preference for the C(2')-endo conformation (approximately 70%) and a conformation about the glycosidic bond predominantly syn (approximately 90%), hence similar to that in the solid state. However, the conformation of the exocyclic 5'-CH2OH group exhibits only a moderate preference for the gauche+ rotamer (approximately 40%), presumably due to the inability to form the intramolecular hydrogen bond to N(3) in a polar medium. The conformational features are examined in relation to the behavior of 8-substituted purine nucleosides in several enzymatic systems, with due account taken of the steric bulk and electronegativities of the 8-substituents.     

The occurrence of the syn-C3′ endo conformation and the distorted backbone conformations for C4′-C5′ and P-O5′ in oligo and polynucleotides

Abstract

The nucleoside constituents of nucleic acids prefer the anti conformation (1). When the sugar pucker is taken into account the nucleosides prefer the C2′endo-anti conformation. Of the nearly 300 nucleosides known, about 250 are in the anti conformation and 50 are in the syn-conformation, i.e., anti to syn conformation is 5:1. The nucleotide building blocks of nucleic acids show the same trend as nucleosides. Both the deoxy-guanosine and ribo- guanosine residues in nucleosides and nucleotides prefer the syn-C2′endo conformation with an intra-molecular hydrogen bond (for nucleosides) between the O5′- H and the N3 of the base and, a few syn-C3′endo conformations are also observed. Evidence is presented for the occurrence of the C3′endo-syn conformation for guanines in mis-paired double helical right-handed structures with the distorted sugar phosphate C4′-C5′ and P-O5′ bonds respectively, from g+ (gg) and g- to trans. Evidence is also provided for guanosine nucleotides in left-handed double-helical (Z-DNA) oligo and polynucleotides which has the same syn-C3′endo conformation and the distorted backbone sugar-phosphate bonds (C4′-C5′ and P- O5′) as in the earlier right-handed case.     

Structure and conformation of 1-beta-D-ribo furanosyl pyridin-2-one-5-carboxamide: an anti-inflammatory agent

The pyrimidine nucleoside, 1-beta-D-ribofuranosyl pyridine-2-one-5-carboxamide, is an anti inflammatory agent used in the treatment of adjuvant-induced arthritis. It is the 2-one isomer of 1-beta-D-ribofuranosyl pyridine-4-one 5-carboxamide, an unusual nucleoside isolated from the urine of patients with chronic myelogenic leukemia and an important cancer marker. Crystals of 1-beta-D-ribofuranosyl pyridine-2-one-5-carboxamide are monoclinic, space group C2, with the cell dimensions a = 31.7920(13), b = 4.6872 (3), c = 16.1838(11), beta = 93.071(3) degrees , V = 2408.2(2) A(3), D(calc) = 1.496 mg/m(3) and Z = 8 (two molecules in the asymmetric unit). The structure was obtained by the application of direct methods to diffractometric data and refined to a final R value of 0.050 for 1669 reflections with I >or= 3sigma. The nucleoside exhibits an anti conformation across the glycosidic bond (chi(CN) = -15.5 degrees , -18.9 degrees ), a C3 '-endo C2 '-exo [(3)(2)T] ribose pucker and g(+) across the C(4 ')-C(5 ') exocyclic bond. The amino group of the carboxamide group is distal from the 2-one and lacks the intramolecular hydrogen bonding found in the related 2-one molecule. Nuclear magnetic resonance studies shows also an anti conformation across the glycosidic bond but the solution conformation of the furanose ring is not the same as that found in the solid state.     

The occurence of the syn-C3' endo conformation and the distorted backbone conformations for C4'-C5' and P-O5' in oligo and polynucleotides.

The nucleoside constituents of nucleic acids prefer the anti conformation (1). When the sugar pucker is taken into account the nucleosides prefer the C2'endo-anti conformation. Of the nearly 300 nucleosides known, about 250 are in the anti conformation and 50 are in the syn-conformation, i.e., anti to syn conformation is 5:1. The nucleotide building blocks of nucleic acids show the same trend as nucleosides. Both the deoxy-guanosine and riboguanosine residues in nucleosides and nucleotides prefer the syn-C2'endo conformation with an intra-molecular hydrogen bond (for nucleosides) between the O5'-H and the N3 of the base and, a few syn-C3'endo conformations are also observed. Evidence is presented for the occurrence of the C3'endo-syn conformation for guanines in mis-paired double helical right-handed structures with the distorted sugar phosphate C4'-C5' and P-O5' bonds respectively, from g+ (gg) and g- to trans. Evidence is also provided for guanosine nucleotides in left-handed double-helical (Z-DNA) oligo and polynucleotides which has the same syn-C3'endo conformation and the distorted backbone sugar-phosphate bonds (C4'-C5' and P-O5') as in the earlier right-handed case.     

Crystal structure and conformation of 8-(2-hydroxyethylamino) and 8-(pyrrolidin-1-yl) adenosines

In the course of investigation of 8-alkylamino substituted adenosines, the title compounds were synthesized as potential partial agonists for adenosine receptors. The structure determination of these compounds was carried out with the X-ray crystallography study. Crystals of 8-(2-hydroxyethylamino)adenosine are monoclinic, space group P 2(1); a = 7.0422(2), b = 11.2635(3), c = 8.9215(2) A, beta = 92.261(1) degrees, V = 707.10(3) A3, Z = 2; R-factor is 0.0339. The nucleoside is characterized by the anti conformation; the ribose ring has the C(2')-endo conformation and gauche-gauche form across C(4')-C(5') bond. The molecular structure is stabilized by intramolecular hydrogen bond of N-HO type. Crystals of 8-(pyrrolidin-1-yl)adenosine are monoclinic, space group C 2; a = 19.271(1), b = 7.3572(4), c = 11.0465(7) A, beta = 103.254(2), V = 1524.4(2) degrees A3, Z = 4; R-factor is 0.0498. In this compound, there is syn conformation of the nucleoside; the ribose has the C(2')-endo conformation and gauche -gauche form across C(4')- C(5') bond. The molecular structure is stabilized by intramolecular hydrogen bond of O-HN type. For both compounds, the branching net of intermolecular hydrogen bonds occur in the crystal structures.     

NMR SOLUTION STRUCTURE AND CONFORMATIONAL ANALYSIS OF THE CALCIUM RELEASE AGENT CYCLIC ADENOSINE 5′-DIPHOSPHATE RIBOSE (cADPR)

A high-resolution NMR study of the solution structure of the calcium release agent cADPR has been performed. Pseudorotationals analysis reveals that in solution both sugar rings in cADPR adopt predominantly (～75%) South conformations, with the A and N rings adopting approximately ²T₃ (C2′-endo(major)-C3′-exo(minor) and ⁴ ₃T (C3′-exo-C4′-endo) conformations, respectively. The backbone torsion angles β and γ have also been determined. While the minor North conformers were not observed in the crystal structure of cADPR, the solution values of the major South conformers compare well to those found in crystal structure.     

The dimensions and shapes of the furanose rings in nucleic acids

A survey was made of the geometry of furanose rings in beta-nucleotides and beta-nucleosides (as monomers related to nucleic acids) for which structures have been determined by X-ray crystallography. Mean values, and estimated standard deviations from them, were calculated for bond-lengths, bond-angles and conformation-angles. For parameters with values dependent on ring-puckering, separate calculations were made for each ring type. (The rings are puckered in one of three conformations: C-2- or C-3-endo or C-3-exo; C-2-exo has not been observed.) The results were used to compute standard furanose rings with C-2-endo, C-3-endo and C-3-exo conformations for use in nucleic acid molecular model-building. The survey also showed that the only other conformation-angle in nucleotides dependent on the furanose ring conformation corresponds to the relative orientation of the purine (or pyrimidine) base and the ring.     

Solution and Solid State Structure of 2′,5′-BIS-(O-Trityl)-3′-Oximinouridine

Abstract

Comparison of the solution (in CDCl₃ at 500 MHz¹H NMR) and X-ray crystal studies of 3′-oximinouridine 1 shows in general good agreement with the high anti glycosidic angle and in the conformation about C4′-C5′. The sugar pucker (C2′-endo) is qualititatively identical in both cases. This is the first example of a conformationally sugar-rigid nucleoside in which the rigidity arises from the sp² character of an endocyclic carbon (i.e. C3′), not from the strain due to the ring fusion (see ref. 7 for conformationally strained nucleosides).     

NMR conformational analysis of p-tolyl furanopyrimidine 2'-deoxyribonucleoside and crystal structure of its 3',5'-di-O-acetyl derivative

The conformation of a representative molecule of a new, potent class of antiviral-active modified nucleosides is determined. A bicyclic nucleoside, 3-(2'-deoxy-beta-D-ribofuranosyl)-6-(4-methylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one, shows C2'-endo and C3'-endo ribose conformations in solution (63:37, 37 degrees C; DMSO-d6), as determined by 1H NMR studies. The crystal structure of a 3',5'-di-O-acetyl-protected derivative (monoclinic, P21, a/b/c= 6.666(1)/12.225(1)/24.676(2) A, beta=90.24(1) degrees , Z=4) shows exclusively C2'-endo deoxyribose puckering. The base is found in the anti position both in solution and in crystalline form.     

A purine nucleoside unequivocally constrained in the syn form. Crystal structure and conformation of 8-(alpha-hydroxyisopropyl)-adenosine

Crystals of 8-(alpha-hydroxyisopropyl)-adenosine dihydrate, C13H19N5O5.2H2O, belong to the monoclinic space group P21. Cell dimensions are a = 8.259 (1), b = 11.117 (2), c = 9.663 (1) A, beta = 109.65 (2) degrees. Intensity data were collected on a four-circle diffractometer and the structure was solved by direct methods. Block diagonal least-squares refinement led to R = 0.031 for 1467 reflections. The glycosyl torsion angle chiCN is 241.4 degrees, corresponding to a syn conformation. The conformation of the exocyclic C(4')-C(5') bond is gauche-gauche and the sugar pucker is C(2') endo. It is considered that the bulky, tetrahedral, neutral 8-substituent, with an effective van der Waals radius of 3.5--4.0 A, provides an adenosine analogue which should exhibit the syn conformation about the glycosidic bond in solution as well as in solid state, irrespective of the nature of the sugar pucker. It should therefore be suitable for studies of interactions with enzyme systems requiring the anti conformation of the nucleoside or nucleotide.     

1H-, 13C-, 31P-NMR studies and conformational analysis of NADP+, NADPH coenzymes and of dimers from electrochemical reduction of NADP+.

All H,H, H,P and several C,P coupling constants, including those between C-4' and the vicinal phosphorus atom, have been determined for NADP+, NADPH coenzymes and for a 4,4-dimer obtained from one-electron electrochemical reduction of NADP+. From these data the preferred conformation of the ribose, that of the 1,4-dihydronicotinamide rings, and the conformation about bonds C(4')-C(5') and C(5')-O(5') were deduced. The preferred form of the 1,4- and 1,6-dihydropyridine rings and the conformation about the ring-ring junction were also obtained for all the other 4,4- and 4,6-dimers formed in the same reduction. All the dimers show a puckered structure, i.e., a boat form for the 1,4- and a twist-boat for the 1,6-dihydronicotinamide ring; both protons at the ring-ring junctions are equatorial and have preferred gauche orientation. On the contrary, the reduced coenzyme NADPH displays a planar or highly flexible conformation, rapidly flipping between two limiting boat structures. The conformation of the ribose rings, already suggested for the NADP coenzymes to be an equilibrium mixture of C(2')-endo (S-type) and C(3')-endo (N-type) puckering modes, has been reexamined by using the Altona procedure and the relative proportion of the two modes has been obtained. The S and N families of conformers have almost equal population for the adenine-ribose, whereas for the nicotinamide-ribose rings the S-type reaches the 90%. The rotation about the ester bond C(5')-O(5') and about C(4')-C(5'), defined by torsion angles beta and gamma respectively, displays a constant high preference for the trans conformer beta t (75-80%), whereas the rotamers gamma are spread out in a range of different populations. The values are distributed between the gauche gamma + (48-69%) and the trans gamma t forms (28-73%). The gamma + conformer reaches a 90% value in the case of NADP+ and NMN+. The conformations of the mononucleotides 5'-AMP, NMN+ and NMNH were also calculated from the experimental coupling constant values of the literature.     

A comparison of the conformations adopted by some 5-bromovinyl-2''-deoxyuridines and a correlation with their antiviral properties: an X-ray study.

Crystal structures of (Z)-5-(2-bromovinyl)-2'-deoxyuridine, 3',5'-di-O-acetyl-(E)-5-(2-bromovinyl)-2'-deoxyuridine and 3',5'-di-O-p-chlorobenzoyl-5-(2-dibromovinyl)-2'-deoxyuridine are compared with each other and with that of the most potent antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (E-BVDU) reported earlier. A comparison of the conformation of 3',5'-di-O-acetyl-pyrimidine nucleoside structures in which intermolecular hydrogen bond network formation is minimized, with those of their parent compounds has shown that the greatest change in rotation about the glycosyl bond and in the sugar ring pucker is exhibited by E-BVDU. Upon acylation this molecule changes from C2'-endo/C3'-exo conformation to C3'-endo/C4'-exo conformation. The relevance of these structures upon the biological activity of the nucleosides and in particular to their ability to be a substrate for thymidine kinase is discussed.