William H. Ojala

The X-ray Crystal Structure of the Sulfonated Azo Dye Congo Red, a Non-Peptidic Inhibitor of HIV-1 Protease which also Binds to Reverse Transcriptase and Amyloid Proteins

Congo Red is a sulfonated azo dye and widely used biological stain that has recently been the focus of intense interest because it has been shown to bind to proteins involved in viral recognition and replication. Congo Red also finds wide use as a histological stain for amyloid proteins of the type found in neurodegenerative conditions such as Alzheimers disease, transmissible spongiform encephalopathies in cattle and mink, and scrapie in sheep. Congo Red has been demonstrated to protect normal prion protein from being converted to the protease-resistant form, an important step in the pathology of the so-called ‘slow viral’ diseases. The range of biological molecules to which Congo Red binds makes it an important lead compound in drug development, for example in the development of new anti-HIV and anti-Alzheimers therapeutic agents. In this report we present the first high-resolution structure of Congo Red: the low-temperature (173 K) X-ray crystal structure determination of its calcium salt. Two conformations of the molecule are found in the same crystal structure, one in which the central biphenyl group assumes a twisted (25°) conformation, and one in which the biphenyl group is planar and is located on a crystallo-graphic inversion centre. In both conformations the sulfonate groups are oriented anti with respect to the long molecular axis and assume eclipsed conformations with respect to the naphthalene rings. A comparison is made with a published structure [Turned, W.G., and Finch, J.T. (1992) J Mol Biol 227: 1205-1223] in which Congo Red is bound to porcine insulin, this complex serving as a model for amyloid binding. The results illustrate the conformational flexibility possessed by the biphenyl spacer, which allows the hydrophobic portion of the molecule to assume an optimum fit in the hydrophobic binding pockets of target proteins. A model is presented for the binding of Congo Red to the HIV protease in which the sulfonate groups interact with the side-chains of arginine residues. This proposed binding mode is consistent with the observed binding for other sulfonated aromatic inhibitors such as Evans Blue.

Intermolecular interactions of sulfonated azo dyes: crystal structures of the diammonium, dilithium, magnesium and calcium salts of 7-hydroxy-8-(phenylazo)-1,3-naphthalenedisulfonic acid(Orange G)

The crystal structures of four salts containing the Orange G dianion have been determined, three at low temperature. Molecular geometry and conformation of the dye molecule are closely similar from structure to structure. In each case, the molecule exits as the hydrazo tautomer rather than as the azo tautomer. A recurring close intermolecular contact is a bridging interaction in which two water molecules coordinated to a given metal atom are hydrogen bonded to two atoms of a single sulfonate group

Crystal structures and physical chemical properties of nedocromil zinc heptahydrate and nedocromil magnesium pentahydrate

The crystal structure of one of the hydrated forms of nedocromil zinc, the heptahydrate, and that of one of the hydrated forms of nedocromil magnesium, the pentahydrate, have been determined. Crystal data: zinc salt,a=11.769(3),b=7.000(2),c=14.022(4); Å; β=105.35(2)°; monoclinic, space groupP21,Z=2;magnesium salt,a=7.460(1),b=10.233(2),c=13.934(2) Å, α=86.54(1)°, β=79.74(1)°, γ=77.25(1)°; triclinic, space groupPĪ,Z=2. The major differences between the crystal structures are the environment and bonding of the cations. The zinc cation is linked directly to the carbonyl oxygen of the pyridone ring and to five water molecules in an octahedral coordination. The magnesium cation is linked directly to two different carboxyl oxygens, one in asyn orientation and the other in ananti orientation in different asymmetric units and to four water molecules in an octahedral coordination. Thermal analytical methods show that the zinc salt hydrate undergoes thermal dehydration at lower temperatures than the magnesium salt hydrate. This behavior may be related to the presence of continuous water channels in the zinc salt hydrate and to their absence in the magnesium salt hydrate. For each salt hydrate 1 mole of water is lost at a higher temperature than the other waters.

The crystal structures of p-iodo-N-(p-cyanobenzylidene)aniline and p-cyano-N-(p-iodobenzylidene)aniline

The crystal structures of the isomers NC–C6H4–CH=N–C6H4–I (CN/I) and I–C6H4–CH=N–C6H4–CN (I/CN) have been determined. CN/I is triclinic, space group P1¯ with a = 7.504(3), b = 11.936(4), c = 7.304(2) Å, α = 93.09(2), β = 110.49(2), γ = 99.04(2)°, V = 601.1(3) Å3, Z = 2, and Dx = 1.818(1) g cm−3. In both compounds there are chains of molecules held together by CN···I interactions, with N···I distances of 3.15 and 3.26 Å, respectively. The chains form similar two-dimensional sheets, which, however, stack differently in the two compounds.

Crystal structure of nedocromil sodium heptahemihydrate and its comparison with that of nedocromil sodium trihydrate

The crystal structure of one of the hydrated forms of nedocromil sodium, the heptahemihydrate, has been determined. Crystal data:a=26.687(5),b=29.479(8),c=6.394(3) Å, orthorhombic, space groupAba2,Z=8. This structure is compared with the previously determined structure of the trihydrate [Freer, A. A., Payling, D. W., and Suschitzky, J. L.,Acta Crystallogr.1987,C43, 1900–1905]. The two structures differ in the molecular conformation of the nedocromil anion, the intensity of color, the coordination of the sodium ions, and the environment of the water molecules. In the heptahemihydrate two of the water molecules from dimers, whereas the remaining water molecules form a two-dimensional network consisting of a pentameric chain in one direction and an infinite chain in the other. From another viewpoint, 5 1/2 water molecules in the heptahemidydrate are present in the first coordination sphere of the sodium ions, whereas the remaining two water molecules are present as “lattice” water in the crystal.

Synthesis and dopamine receptor modulating activity of unsubstituted and substituted triproline analogues of L-prolyl-L-leucyl-glycinamide (PLG)

Triprolines Pro-Pro-Pro-NH2 (4), Pro-Pro-D-Pro-NH2 (5), Pro-Pro(trans-3-Me)-D-Pro-NH2 (6), and Pro-Pro(cis-3-Me)-D-Pro-NH2 (7) were made as conformationally constrained analogues of Pro-Leu-Gly-NH2. Triprolines 4-6 produced significant increases in the high- and low-affinity state ratio (RH/RL) of the dopamine receptor, but only 4 was found to increase apomorphine induced rotations in 6-hydroxydopamine-lesioned rats.

Crystal and molecular structures of derivatives formed by reaction between toluenesulfonhydrazide and D-glucose, D-galactose, and L-arabinose

Derivatives formed by reaction of toluenesulfonhydrazide with D-glucose, D-galactose, and L-arabinose are shown by X-ray crystal structure analysis to be N-glycosides rather than open-chain hydrazones in the solid state. All three sugar derivatives assume the 4C1 pyranosyl form, and in all three cases the orientation of the N-glycosidic linkage is equatorial. The gauche conformation of the glucoside and galactoside at the N(2)–N(1)–C(1)–C(2) linkage allows formation of an intramolecular hydrogen bond between the O(2) hydroxyl group and a sulfonyl oxygen atom, but no corresponding intramolecular interaction is found in the arabinoside due to its trans conformation at this linkage. In both the galactoside and arabinoside an S–O bond is eclipsed with the phenyl ring, but in the glucoside the phenyl ring assumes a staggered orientation with respect to the S–O bonds. Intermolecular hydrogen bonding interactions bind the molecules together to form alternating layers of hydrophilic groups (the pyranosyl rings) and hydrophobic groups (the aryl rings) in the crystal.

Interactions between sulfonated azo dyes and biomolecules: orange G/adenine and orange G/cytosine salts

The disulfonated azo dye Orange G [the disodium salt of 7-hydroxy-8-(phenylazo)-1,3-naphthalene-disulfonic acid] forms salts with adenine and cytosine on co-crystallization from aqueous HCl. The 1:2 dye:adenine crystal, 2C 5 H 6 N 5 + .C 16 H 10 N 2 O 7 S 2 2- .5H 2 O, is a pentahydrate and the 1:2 dye:cytosine crystal, 2C 4 H 6 N 3 O + .C 16 H 10 N 2 O 7 S 2 2- .H 2 O, is a monohydrate. In the solid state the dye is found to exist predominantly as the hydrazo, rather than the azo, tautomer. In both structures, one of the protonated nucleotide bases approaches close to a sulfonate group of the dye in an «edge-on» fashion

Isomeric Schiff bases related by dual imino-group reversals

Two isomeric pairs of Schiff bases, N,N-bis(2-methoxybenzylidene)-p-phenylenediamine, C(22)H(20)N(2)O(2), (I), and 2,2-dimethoxy-N,N-(p-phenylenedimethylene)dianiline, C(22)H(20)N(2)O(2), (II), and (E,E)-1,4-bis(3-iodophenyl)-2,3-diazabuta-1,3-diene (alternative name: 3-iodobenzaldehyde azine), C(14)H(10)I(2)N(2), (III), and N,N-bis(3-iodophenyl)ethylenediimine, C(14)H(10)I(2)N(2) [JAYFEV; Cho, Moore & Wilson (2005). Acta Cryst. E61, o3773-o3774], differ pairwise only in the orientation of their imino linkages and in all four individual cases occupy inversion centers in the crystal, yet all four compounds are found to assume unique packing arrangements. Compounds (I) and (II) differ substantially in molecular conformation, possessing angles between their ring planes of 12.10 (15) and 46.29 (9) degrees , respectively. Compound (III) and JAYFEV are similar to each other in conformation, with angles between their imino linkages and benzene rings of 11.57 (15) and 7.4 (3) degrees , respectively. The crystal structures are distinguished from each other by different packing motifs involving the functional groups. Intermolecular contacts between methoxy groups define an R(2)(2)(6) motif in (I) but a C(3) motif in (II). Intermolecular contacts are of the I...I type in (III), but they are of the N...I type in JAYFEV.

Carbohydrates with relevance to the structure of glycosaminoglycans: The crystal structures of 2-deoxy-2-(sulfoamino)-α-d-glucopyranose sodium salt dihydrate, 2-amino-2-deoxy-α,β-d-glucopyranose 3-(hydrogen sulfate) monohydrate, and 2-amino-2-deoxy-α-d-glucopyranose 6-(hydrogen sulfate) monohydrate

Abstract The X-ray crystal structures of the glycosaminoglycan-related monosaccharides 2-deoxy-2-(sulfoamino)-α- d -glucopyranose sodium salt dihydrate, 2-amino-2-deoxy-α,β- d -glucopyranose 3-(hydrogen sulfate) monohydrate, and 2-amino-2-deoxy-α- d -glucopyranose 6-(hydrogen sulfate) monohydrate have been determined at 173 K. In the solid state, the 3-sulfated and 6-sulfated compounds assume the expected zwitterionic form. The 2(N)- and 6-sulfate crystal structures contain only the α-anomers, but the 3-sulfate crystal structure includes both the α- and β-anomers, as well as two different orientations of the hydroxymethyl group. The sodium ion in the 2(N)-sulfate structure is sixfold coordinated, with two water molecules, a sulfate oxygen, a ring oxygen, and two hydroxyl oxygens serving as electron donors. The 2(N)-sulfate group makes direct contact with the sodium ion and also makes indirect contact with it through mediating water molecules. In the 3-sulfate structure, the sulfate group participates in a close intramolecular contact with the protonated amino group at C-2. In all three structures the sulfate oxygens engage in close intermolecular interactions with -NH3+ and -OH groups and with water molecules, although the sole sulfate-water approach in the 6-sulfate structure is exceptional in not being very close (> 3.0 A). Selected IR and NMR data are presented.