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H L Ammon

Publications and source records attributed to H L Ammon.

At least 19 recordsLinked to original sources

A third blind test of crystal structure prediction.

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

Algorithms↗

A test of crystal structure prediction of small organic molecules.

A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing, the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as "correct". One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol(-1) of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.

Journal Article↗

Trichoverroid stereoisomers.

Trichoverroids, which lie along the biosynthetic path between the simple and the macrocyclic trichothecenes, have been characterized previously as sets of diastereomers that have the S-configuration at C-6' and are epimeric at C-7'. An isolate of Myrothecium verrucaria (ATCC 20540), which is the only species of Myrothecium reported to produce the macrocyclic trichothecene isororidin E (3a), produces trichoverrols (1) and trichoverrins (2) that are epimeric at C-7' but that have R-configurations at the C-6' centers. Also reported are several additional naturally occurring C6'R-series trichoverroids that have varied structural modifications, including several E,Z-isomers 7-9, 9 beta,10 beta-epoxides 11a and b, 12,13-deoxyisotrichoverrin B (10), and 8 alpha-hydroxyisotrichoverrin A (12).

Crystallography, X-Ray↗

Thiodicarb.

Dimethyl N,N'-[thiobis(methyliminocarbonyloxy)] bis-(ethanimidothiolate), C10H18N4O4S3, is an example of a sulfenylated biscarbamate insecticide. The molecule has an approximate twofold axis through the central S atom which joins the two methyliminocarbonyloxyethanimidothiolate units. One of the two arms is planar in the crystal. Semi-empirical geometry optimization for an isolated molecule favors a model with both arms planar and, thus, crystal packing may be responsible for the observed non-planarity in one arm. Bond lengths and angles have similar values to those of the 'monomeric' carbamate insecticide methomyl.

Crystallography, X-Ray↗

Photoinstability of some tyrphostin drugs: chemical consequences of crystallinity.

PURPOSE: The purpose of this work was to study the photostability of the antiproliferative tyrphostin drug compounds RG 13022(I) and RG 14620(II) as a part of preformulation program. METHODS: The compounds were exposed to cool white fluorescent light in solution as well as in the solid state and analyzed by HPLC. The degradation products were isolated chromatographically and their structures determined by spectroscopic methods. X-ray crystallographic analyses of the above compounds and their solid state degradation products were carried out to understand the mechanism of photodegradation. RESULTS: The compounds were found to undergo efficient photochemical transformations in solution as well as in the solid state. The degradation in the solution was due to the photoisomerization into their E-isomers (III and IV). The solid state photodegradation products were [2 + 2]-cycloaddition products (V and VI). The stereochemistry of the photocycloaddition products was indicative of the crystal packing of their monomeric precursors. The photocycloaddition product of RG 13022 possesses the head-to-tail linkage as expected from the head-to-tail packing of RG 13022 molecules in the crystal. The photocycloaddition product of RG 14620, however, was found to involve head-to-head linkage in agreement with the head-to-head crystal packing of RG 14620. CONCLUSIONS: Drug compounds containing open chain olefinic double bonds could be sensitive to mild condition of light in the solid state if the distance between the two double bonds in the crystal approaches 4.2 degrees A and they have suitable UV absorption characteristics. Attractive interactions between chlorine atoms have significant influence in controlling the crystal packing of chlorinated aromatic compounds.

Alkenes↗

Refined crystal structure of Acinetobacter glutaminasificans glutaminase-asparaginase.

The crystal structure of glutaminase-asparaginase from Acinetobacter glutaminasificans has been reinterpreted and refined to an R factor of 0.171 at 2.9 A resolution, using the same X-ray diffraction data that were used to build a preliminary model of this enzyme [Ammon, Weber, Wlodawer, Harrison, Gilliland, Murphy, Sjölin & Roberts (1988). J. Biol. Chem. 263, 150-156]. The current model, which does not include solvent, is based in part on the related structure of Escherichia coli asparaginase and is significantly different from the structure of the enzyme from A. glutaminasificans described previously. The reason for the discrepancies has been traced to insufficient phasing power of the original heavy-atom derivative data, which could not be compensated for fully by electron-density modification techniques. The corrected structure of A. glutaminasificans glutaminase-asparaginase is presented and compared with the preliminary model and with the structure of E. coli asparaginase.

Journal Article↗

Structural characterization of Pseudomonas 7A glutaminase-asparaginase.

The amino acid sequence and a 2-A-resolution crystallographic structure of Pseudomonas 7A glutaminase-asparaginase (PGA) have been determined. PGA, which belongs to the family of tetrameric bacterial amidohydrolases, deamidates glutamine and asparagine. The amino acid sequence of PGA has a high degree of similarity to the sequences of other members of the family. PGA has the same fold as other bacterial amidohydrolases, with the exception of the position of a 20-residue loop that forms part of the active site. In the PGA structure presented here, the active site loop is observed clearly in only one monomer, in an open position, with a conformation different from that observed for other amidohydrolases. In the other three monomers the loop is disordered and cannot be traced. This phenomenon is probably a direct consequence of a very low occupancy of product(s) of the enzymatic reaction bound in the active sites of PGA in these crystals. The active sites are composed of a rigid part and the flexible loop. The rigid part consists of the residues directly involved in the catalytic reaction as well as residues that assist in orienting the substrate. Two residues that are important for activity residue on the flexible loop. We suggest that the flexible loops actively participate in the transport of substrate and product molecules through the amidohydrolase active sites and participate in orienting the substrate molecules properly in relation to the catalytic residues.

Amidohydrolases↗

Structure of 1,1,5,5-tetranitro-[4]peristylane. Structure solution from molecular packing analysis.

The structure of the title compound, decahydro-2,2,5,5-tetranitro-1,6:3,4-dimethanocyclobuta[1,2: 3, 4]dicyclopentene, C12H12N4O8, was solved with the molecular packing program MOLPAK, starting with an AM1-geometry-optimized model of an isolated molecule. The 20 best predicted crystal structures from the MOLPAK procedure were subjected to lattice energy refinement with the WMIN program. A structure-factor calculation with the top MOLPAK/WMIN derived structure and the 197 Fo data to sin theta/lambda = 0.324 A-1 (theta = 30 degrees) gave an R value of 0.29. Final R = 0.057, wR = 0.067 for 730 reflections with I > 3 sigma (I). There are no unusual intermolecular distances and crystal packing is normal.

Bridged-Ring Compounds↗

Structure and function of the xenobiotic substrate binding site of a glutathione S-transferase as revealed by X-ray crystallographic analysis of product complexes with the diastereomers of 9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene.

The three-dimensional structures of isoenzyme 3-3 of glutathione (GSH) transferase complexed with (9R,10R)- and (9S,10S)-9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene [(9R,10R)-2 and (9S,10S)-2], which are the products of the addition of GSH to phenanthrene 9,10-oxide, have been determined at resolutions of 1.9 and 1.8 A, respectively. The structures indicate that the xenobiotic substrate binding site is a hydrophobic cavity defined by the side chains of Y6, W7, V9, and L12 from domain I (the GSH binding domain) and I111, Y115, F208, and S209 in domain II of the protein. All of these residues are located in variable-sequence regions of the primary structure of class mu isoenzymes. Three of the eight residues (V9, I111, and S209) of isoenzyme 3-3 that are in direct van der Waals contact with the dihydrophenanthrenyl portion of the products are mutated (V9I, I111A, and S209A) in the related isoenzyme 4-4. These three residues are implicated in control of the stereoselectivity of the class mu isoenzymes. The hydroxyl group of Y115 is found to be hydrogen-bonded to the 10-hydroxyl group of (9S,10S)-2, a fact suggesting that this residue could act as an electrophile to stabilize the transition state for the addition of GSH to epoxides. The Y115F mutant isoenzyme 3-3 is about 100-fold less efficient than the native enzyme in catalyzing the addition of GSH to phenanthrene 9,10-oxide and about 50-fold less efficient in the Michael addition of GSH to 4-phenyl-3-buten-2-one. The side chain of Y115 is positioned so as to act as a general-acid catalytic group for two types of reactions that would benefit from electrophilic assistance. The results are consistent with the notion that domain II, which harbors most of the variability in primary structure, plays a crucial role in defining the substrate specificity of class mu isoenzymes.

Animals↗

Structure of a 2-arylquinoline dimer, a compound with a new ring system.

The title compound, 6,15-dimethyltribenzo-[c,f,j]naphtho[1,2,3,4-lmn][2,7]phe nanthroline was obtained in low yield from the reaction of 2-(4-methylphenyl)quinoline and various aryllithiums. The compound is a 'dimer' in which two phenylquinoline units are joined by three bonds; the dimer has exact twofold symmetry. Non-bonded interactions produce substantial out-of-plane distortions. Bond lengths between the two phenylquinoline halves suggest that the two phenylquinoline pi-electron systems are more-or-less undisturbed and linked by single bonds. Molecular-mechanics optimizations of models with inversion (1) and twofold symmetry suggest that the latter conformation is the more stable of the two to a slight extent.

Crystallography, X-Ray↗

Structure of 2-methoxycarbonyl-1,4-dinitrocubane.

The title compound, methyl 2,7-dinitropentacyclo-[4.2.0.0(2,5).0(3,8).0(4,7)]octane-1-carboxy late, is one of the few examples of cubanes with substituents on adjacent C atoms. There are two enantiomeric molecules per asymmetric unit in a structure with a noncentrosymmetric space group, P2(1)2(1)2. The molecules differ primarily in the conformations of the C-NO2 groups adjacent to the methoxycarbonyl sustituents. The 1,2-disubstituted cubane C-C bonds average 1.564 A, a typical value for an unsubstituted cubane bond.

Crystallography, X-Ray↗

Structure and absolute configuration of a high affinity 5-HT3 receptor antagonist, (5aS,9aS)-N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2-chloro- 5a,6,7,8,9,9a-hexahydro-4-dibenzofurancarboxamide hydrochloride.

The absolute configuration was established as (S,S,S) by the R-factor test and by careful measurement of 197 enantiomorph-sensitive Friedel pairs of reflections. The determination also confirms the absolute stereochemistry of (-)-3-aminoquinuclidine, a compound used in the preparation of the title material. The cyclohexane/tetrahydrofuran ring fusion is cis. The quinuclidine moiety has almost perfect threefold symmetry; the front and rear halves are twisted about this axis by 15 degrees. Quinuclidine-N--H ... Cl- and amide-N--H ... Cl- hydrogen bonds link screw-dyad-related molecules along the b axis.

Amides↗

2,3,4-Tri-O-acetyl-1,6-anhydro-beta-D-mannopyranose, an artifact produced during carbohydrate analysis. A total synthesis of 2,3,5-tri-O-acetyl-1,6-anhydro-beta-D-mannofuranose.

This study confirms that 2,3,4-tri-O-acetyl-1,6-anhydro-beta-D-mannopyranose is an artifact produced during carbohydrate analysis. A new synthesis of 2,3,5-tri-O-acetyl-1,6-anhydro-beta-D-mannofuranose is also described, and a novel dimer, 1,6':6,1'-dianhydro-2,3:2',3'-di-O-isopropylidene-5,5'-di-O-(1-methox yethyl)-di - alpha-D-mannofuranose, has been isolated. The structure of the dimer is confirmed by X-ray analysis of a derivative, 1,6':6,1'-dianhydro-2,3:2',3'-di-O-isopropylidene-di-alpha-D-mannofur anose.

Artifacts↗

Structures of secocubane and nortwistbrendane derivatives.

(I): 4,7-Dichloro-1-cyano-N-isopropyltetracyclo-[4.2.0.0(2,5).0(3,8)] octane-4-carboxamide, C13H14Cl2N2O, M(r) = 285.17, orthorhombic, Fdd2, a = 34.012 (1), b = 15.791 (2), c = 10.899(1)A, Z = 16, D chi = 1.29 g cm-3, Cu K alpha (lambda = 1.5418 A), mu = 39.2 cm-1, F(000) = 2368, T = 293 K, 1504 reflections with I > 3 sigma(I), R = 0.042. (II): 4,7-Dichloro-N-isopropyl-10-oxo-9-oxatetracyclo [4.4.0.0(2,5).0(3,8)]decane-4-carboxamide, C13H15Cl2NO3, M(r) = 304.17, monoclinic, P2(1)/a, a = 9.902(2), b = 9.381(2), c = 15.174(2) A, beta = 103.25(1) degrees, Z = 4, D chi = 1.47 g cm-3, Cu K alpha (lambda = 1.5418 A), mu = 43.1 cm-1, F(000) = 632, 2107 reflections with I > 3 sigma(I), R = 0.036. (I) represents the first crystallographic example of a secocubane. The nonbonded distances (C4...C7) are 2.742 (5) and 2.717(3) A in (I) and (II). C--C distances in the cage portions of the molecules are typical of cubanes.

Bridged-Ring Compounds↗

Structure of RG-12561 dichloromethane solvate and a diastereomer.

(III): [4 alpha,6 beta(E)]-(+-)-6-(2-[2-(4-Fluoro-3-methylphenyl)- 4,4,6,6-tetramethyl-1-cyclohexen-1-yl]ethenyl)-4-hydroxytetrahy dro pyran-2-one (RG-12561) dichloromethane solvate, 2C24H31FO3.CH2-Cl2, Mr = 857.94, triclinic, Pl, a = 11.7413 (5), b = 13.0279 (5), c = 16.2332 (9) A, alpha = 99.456 (4), beta = 94.217 (4), gamma = 101.893 (4) degrees, V = 2381.9 (4) A3, Z = 4 [four molecules of (III)+two molecules of solvent per unit cell], Dx = 1.195 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 16.69 cm-1, F(000) = 912, T = 293 K, final R = 0.053, wR = 0.060 for 4031 reflections with I greater than 3 sigma(I). (IV): [4 beta,6 alpha(E)]-(+-)-6-(2-[2- (4-Fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclo-hexen-1-yl]e thenyl)-4- hydroxytetrahydropyran-2-one, C24H31FO3, Mr = 386.51, triclinic, Pl, a = 6.054 (2), b = 12.931 (2), c = 14.838 (3) A, alpha = 67.70 (2), beta = 85.75 (2), gamma = 82.85 (2) degrees, V = 1066.0 (8) A3, Z = 2, Dx = 1.203 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 6.86 cm-1, F(000) = 414, T = 293 K, final R = 0.073, wR = 0.081 for 1588 reflections with I greater than 3 sigma(I). (III) is a potent HMG-CoA reductase inhibitor and has the potential to function as a superior hypocholesterolemic agent; (IV) lacks this activity. (III) and (IV) have different conformations and molecular-model calculations suggest that crystal-packing effects are primarily responsible for the overall conformation of (IV). The principal intermolecular contacts are hydrogen bonds of the type O-H...O = C.

Anticholesteremic Agents↗

The structure of celiprolol.

The crystal structure and nuclear magnetic resonance (NMR) spectra and assignments of celiprolol, N'-[3-acetyl-4[3-[N-t-butylamino-2-hydroxypropoxy]phenyl]-N,N- diethylurea, are reported. Celiprolol crystallizes in the monoclinic space group, P2(1)/a, with a = 9.081(2), b = 13.800(4), and c = 17.471(5) A and beta = 95.04(2)degrees. Structure was solved by direct methods; structure refinement to R of 0.058. Intermolecular hydrogen-bonding in the crystal is discussed. The 1H, 13C, and two-dimensional (2D) NMR spectra of the hydrochloride have been obtained and definitive signal assignments made.

Adrenergic beta-Antagonists↗

Structure of a lactone, 2,4,6-trideoxy-4,6-dimethyl-2-(2-oxopropyl)-7-O- (phenylmethyl)-L-glycero-D-manno-heptono-1,5-lactone 3-(3,5-dinitrobenzoate).

C26H28N2O10, Mr = 528.5, triclinic, P1, a = 9.524 (1), b = 11.8187 (8), c = 12.615 (1) A, alpha = 66.512 (7), beta = 83.321 (9), gamma = 88.758 (8) degrees, V = 1293.0 (4) A3, Dx = 1.357 g cm-3, Z = 2, lambda(Cu K alpha) = 1.54178 A, mu = 8.99 cm-1, F(000) = 556, T = 293 K, final R = 0.039, wR = 0.048 for 2425 reflections with I greater than 3 sigma(I). The tetra-substituted valerolactone ring has a boat conformation and the relative stereochemistries of the three pairs of adjacent substituents are cis-trans-trans.

Lactones↗

Structure of a lactone, (3 alpha,4 alpha,6 alpha)-4-(tert- butyldimethylsiloxy)-3,4,5,6-tetrahydro-6-methyl-3-(2-oxopropyl)- 2H- pyran-2-one.

C15H28O4Si, Mr = 300.5, monoclinic, P2(1)/a, a = 11.194 (4), b = 10.944 (3), c = 14.815 (5) A, beta = 95.01 (3) degrees, V = 1808 (2) A3, Dx = 1.104 g cm-3, Z = 4, lambda(Mo K alpha) = 0.71069 A, mu = 1.43 cm-1, F(000) = 656, T = 293 K, final R = 0.052, wR = 0.058 for 1630 reflections with I greater than 3 sigma(I). The valerolactone ring is in a boat conformation and the three ring substituents are cis.

Models, Molecular↗