George I. Birnbaum

Conformations of Ammonium 3-Deoxy-D-manno-2-octulosonate (KDO) and Methyl α- and β-Ketopyranosides of KDO: X-Ray Structure and 1H NMR Analyses

Abstract Ammonium 3-deoxy-D-manno-2-octulosonate monohydrate (KDO) crystallizes in the orthorhombic space group P212121, and the cell dimensions are a - 6.9700(4)A, b = 7.7230(4) A, c = 23.4067 (12) A. X-ray intensity data were measured on a diffractometer, and the structure was determined by direct methods. Least-squares refinement, which included all hydrogen atoms, converged at R = 0.034 for 1526 observed reflections. The pyranose ring exists in an almost perfect 5C2 (D) chair conformation. The COO-, 4-OH and 6-CHOHCH2OH groups are In equatorial orientation, while the 2-OH and 5-OH groups are axial. The solution conformations of the ammonium salts of methyl α- and β-ketopyranosides of KDO were determined by high-resolution 1H NMR spectroscopy. The conformation of the ethylene glycol side chain in the α-methyl glycopyranoside of KDO was found to be indistinguishable from that in the solid state. However, the solution conformation of the side chain is different in the β-anomer, possibly indicative of an ...

Mechanism of hydroxylamine mutagenesis. Crystal structure and conformation of 1,5-dimethyl-N4-hydroxycytosine.

The crystal structure of the title compound, which is a formal analogue of 5-methyl-N4-hydroxycytosine nucleosides, has been determined by X-ray diffraction. The space group is P2(1)/c with a = 7.368 (2), b = 12.096 (3), c = 9.192 (4) A, beta = 113.94 (3) degrees. Three-dimensional intensity data were collected with a four-circle diffractometer, and the structure was refined by block-diagonal least-squares to R = 0.053. The compound is in the imino form, and the exocyclic N4-OH is located essentially in the plane of the pyrimidine ring, and syn to the ring (N(3). There is an intramolecular hydrogen bond involving the N(3)-H as donor and O(4) as acceptor, viz. N(3)-H(31)----O(4)-H. With this conformation, which probably prevails also in solution, the compound would be unable to participate in normal Watson-Crick base pairing. It is shown that a similar situation may prevail for N4-hydroxycytosine nucleosides. The implications with regard to the molecular mechanism of hydroxylamine mutagenesis, with particular reference to the T-even bacteriophages, are discussed. Analogous considerations are applied to an examination of the possible behaviour of hydroxylamine-modified adenine nucleosides.

Unusual structural features of 2',3'-dideoxycytidine, an inhibitor of the HIV (AIDS) virus.

The structure and conformation of 2,3-dideoxycytidine, a potent inhibitor of the human immunodeficiency virus, was determined by X-ray crystallography. The nucleoside crystallizes in the tetragonal space group P4(1)2(1)2 with cell dimensions a = b = 8.698(4) and c = 26.155(9) A. Atomic parameters were refined by full-matrix least squares to a final value of R = 0.037 for 1926 observed reflections. The conformation of the furanose ring corresponds to the unusual C3exo/C4endo (3T4) pucker, similar to that found in one of the molecules of 3-azidothymidine (AZT). The glycosidic torsion angle is also smaller than expected. The relevance of these unusual structural features to anti-AIDS activity is assessed.

A purine nucleoside unequivocally constrained in the syn form. Crystal structure and conformation of 8-(α-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.

α-Nucleosides in biological systems: Crystal structure and conformation of α-cytidine

Abstract The structure of α-cytidine, C9H13N3O5, monoclinic with space group C2 and cell parameters a = 20.064 (3) A , b = 7.100 (1) A , c = 7.860 (2) A , β = 104.60 (2)°, Z = 4, was determined by X-ray diffraction using a combination of direct methods, Patterson and difference Fourier techniques and refined by block-diagonal least-squares to a final R of 0.033 for 1002 reflections measured on a diffractometer. The glycosidic torsional angle, χCN = −28.4°, is in the anti region; the sugar pucker is C(2′)exo-C(3′)endo in a nearly pure 32H twist; and the conformation of C(4′)-C(5′) is gauche-gauche. The molecules are bound by hydrogen bonds in the lattice with little likelihood of base-stacking interactions. The molecular features of the compound are compared and contrasted with those of its naturally occurring β-anomer, and some biological implications of this structure, and α-nucleosides in general, are discussed.

Structural Features of 2′,3′-Dideoxy-2′,3′-Didehydrocytidine, A Potent Inhibitor of the HIV (AIDS) Virus

Abstract The structure and conformation of 2′,3′-dideoxy-2′,3′-didehydrocytidine (2′,3′-dideoxycytidin-2′-ene, d4C), a potent inhibitor of the human immunodeficiency virus, was determined by X-ray crystallography. The nucleoside crystallizes in the orthorhombic space group P212121 with cell dimensions a = 8.603(1), b = 9.038(1), c = 25.831(2) A and with two independent molecules in the asymmetric unit (Z = 8). Atomic parameters were refined by full-matrix least squares to a final value of R = 0.033 for 2258 observed reflections. The molecules are quite flexible: in molecule A the glycosyl torsion angle (XCN) is 61.3° and the -CH2OH side chain is in the gauche + orientation while in molecule B XCN = 19.8° and the side chain is trans. The five-membered rings are slightly puckered (∼0.1 A), 04′ being endo in molecule A and exo in molecule B. A mechanism is proposed for the known instability of 2′,3′-unsaturated nucleosides.

Conformations of Acyclonucleosides: Crystal Structure of 9-(4-Hydroxybutyl)Guanine, an Analogue of Acyclovir

Abstract 9-(4-Hydroxybutyl)guanine is an analogue of acyclovir in which the ether oxygen is replaced by a methylene group. Crystals of the monohydrate belong to the monoclinic space group P21/n with a = 4.350 (1), b = 10.859 (1), c = 23.684 (4) A, β = 90.65 (1)°. X-ray intensity data were measured with a diffractometer and the structure was determined by direct methods. Least-squares refinement converged at R = 0.055 for 1982 reflections. The side chain is fully extended and almost perpendicular to the guanine base.

Synthesis of L-Iduronic Acid Derivatives: Crystal Structure of Methyl (Methyl 2,3,4-Tri-O-Acetyl-β-L-Idopyranosid)Uronate

ABSTRACT Several L-iduronic acid derivatives were prepared by chemical synthesis including the reducing sugar, the α– and s-methyl glycosides and L-iduronolactone. The s-methyl glycoside, as well as two isomeric orthoesters, were the unexpected products of glycosylation of methyl (2,3,4-tri-O-acetyl-α-L-idopyranosyl bromide) uronate. EI-MS was used to distinguish between the orthoesters and the glycosides. The crystal structure of the s-methyl glycoside was determined by direct methods and refined by full-matrix least squares to a final value of R = 0.067 for 1739 reflections. The pyran ring was found to occur in the 1C4 conformation, with the three acetoxy substituents in axial orientations. In aqueous solution, the α-anomer of the reducing sodium salt is almost entirely in a 2SO ring conformation and the α-methyl glycoside is an equilibrium mixture of conformations which is sensitive to pH: The s-anomers all have spectral data consistent with predominant or only slightly distorted 1C4 chairs.

Crystallization and preliminary X-ray diffraction study of a xylanase from Trichoderma harzianum

A 20,000 Mr xylanase from Trichoderma harzianum has been purified and crystallized from 20% (w/v) saturated ammonium sulphate solutions. The unit cell is orthorhombic, space group P2(1)2(1)2(1), with unit cell lengths a = 44.2 A, b = 94.1 A, c = 51.6 A. Data from native crystals and several potential heavy-atom derivatives have been collected. An X-ray analysis to at least 2.8 A resolution appears to be feasible.

Structure and conformation of the potent antiherpes agent 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine)

Abstract The structure and conformation of 9-(2-hydroxyethoxymethyl)guanine (Acyclovir), a potent inhibitor of herpes simplex viruses, was determined by X-ray diffraction. The asymmetric unit contains three independent molecules of the nucleoside analogue and two molecules of water. In two of them the acyclic chain at N(9) is partly in the folded form; in the third it is fully extended. Both conformations resemble that of guanosine, and the conformation of all three molecules about the glycosidic bond is in the high anti range. The relevance of the conformational data to the substrate susceptibility of Acyclovir towards kinases, and to its antiviral activity, is examined.