Formation of solid solutions between racemic and enantiomeric citalopram oxalate

The X-ray powder diffractograms of racemic citalopram oxalate and (S)-citalopram oxalate are very similar, but the melting point of the racemate is higher than that of the pure enantiomer. The higher melting point indicates that the racemate is a racemic compound, rather than a conglomerate. The crystal structure of the enantiomer contains two molecules of (S)-citalopram in the asymmetric unit. The conformation of the two molecules is different but they approximate mirror images of each other if the aromatic groups are interchanged. The crystal structure of the racemate is essentially isostructural with that of the enantiomer, having almost the same cell parameters but containing a crystallographic inversion centre that is not retained in the enantiomer structure. The closely-comparable crystal structures permit solid solutions to be formed between racemic and enantiomeric citalopram oxalate. Phase diagrams of the (R)-citalopram and (S)-citalopram oxalate system are constructed, and they show that solid solutions are formed at all ratios of the two enantiomers.     

3-Amino-2-piperidinone-6-carboxylic acid. Molecular structures of cis and trans benzoyl derivatives

The cis (2a) and trans (2b) isomers of methyl 3-benzamido-2-piperidinone-6-carboxylate (Apca) were prepared and separated by fractional recrystallizations. Proton n.m.r. studies in dimethylsulfoxide solution indicate that the six-membered lactam ring adopts a distorted chair conformation with an equatorially oriented benzamido substituent in both 2a and 2b. The carboxyl function also is equatorially oriented in the trans isomer 2b, but is disposed axially in the cis isomer 2a. In the crystal structure, the six-membered lactam ring of 2a is clearly in a boat conformation with the benzamido and carboxyl functions attached to the two apex carbon atoms equatorially. The trans isomer, 2b, exists as two crystallographically independent, conformationally distinct molecules in one unit cell. The lactam ring in both molecules adopts a distorted chair conformation, as is the case in solution, with both the benazamido and carboxyl functions attached equatorially. The rotameric orientation for the endocyclic lactam differs between the two molecules. Both structures show evidence of C-H...O hydrogen bond formation intermolecularly in the solid state. This ability, along with the distinctive conformational features of Apca, may be exploitable in the design of unique features of polypeptides.     

Type II' beta-bend conformation of tert.-butyloxycarbonyl-L-amino-succinyl-L-alanyl-glycine methyl ester in the solid state

Boc-L-Asu-L-Ala-Gly-OMe crystallizes in the monoclinic space group P2(1) with cell dimensions a = 14.315 (3) A, b = 9.280 (2) A, c = 14.358(3) A, beta = 103.63(1) A, V= 1853.4 (9) A3, with two molecules in the asymmetric unit. The conformation of the two molecules is characterized by a type II' beta-bend, similar to that predicted earlier by potential energy calculations, stabilized by an intramolecular hydrogen bond. I.r. and 1H-n.m.r. data show that the folded conformation is also stable in chloroform solution.     

Quantum-chemical and empirical calculations on phospholipids IV. Glycero-phosphorylethanolamine in a quasihexagonal planar lattice

The energetically most stable head group conformations of a racemic mixture of diacyl-glycero-phosphorylethanolamine in a planar quasihexagonal lattice were calculated using empirical 1-6-12 atom-atom potential functions for intra- and intermolecular interactions. The results demonstrate that the conformation of phospholipid head groups in bilayer systems is determined by intramolecular interactions as well as by intermolecular interactions with neighbouring phospholipid molecules and with solvent molecules. The most stable conformers are that with a φ2 = guache^? conformation of the phosphodiester group. All conformers with a φ2 = gauche⁽⁺⁾ or trans conformation have energies more than 15 kcal ☆ mol^?1 above that of the global minimum. The calculated torsional angles ?1 and φ1 are in very good agreement with the results of the X-ray diffraction analysis of 1,2-dilauroyl-DL-phosphatidylethanolamine (DLPE) acetic acid single crystals.     

Interaction of Poliovirus with Its Receptor Affords a High Level of Infectivity to the Virion in Poliovirus Infections Mediated by the Fc Receptor

Poliovirus infects susceptible cells through the poliovirus receptor (PVR), which functions to bind virus and to change its conformation. These two activities are thought to be necessary for efficient poliovirus infection. How binding and conformation conversion activities contribute to the establishment of poliovirus infection was investigated. Mouse L cells expressing mouse high-affinity Fcγ receptor molecules were established and used to study poliovirus infection mediated by mouse antipoliovirus monoclonal antibodies (MAbs) (immunoglobulin G2a [IgG2a] subtypes) or PVR-IgG2a, a chimeric molecule consisting of the extracellular moiety of PVR and the hinge and Fc portion of mouse IgG2a. The antibodies and PVR-IgG2a showed the same degree of affinity for poliovirus, but the infectivities mediated by these molecules were different. Among the molecules tested, PVR-IgG2a mediated the infection most efficiently, showing 50- to 100-fold-higher efficiency than that attained with the different MAbs. A conformational change of poliovirus was induced only by PVR-IgG2a. These results strongly suggested that some specific interaction(s) between poliovirus and the PVR is required for high-level infectivity of poliovirus in this system.     

Self-association of N-protected α-amino acids. Optically active and racemic N-tert-butyloxycarbonyl-alanine

The ir absorption and x-ray diffraction analysis of N-tert-butyloxycarbonyl-DL -alanine (t-Boc-DL -Ala-OH) in the solid state has revealed a new mode of self-association for a N-urethanyl-α-amino acid, i.e., ribbons of hydrogen-bonded cyclic dimers formed through the —COOH groups. In contrast to the recemate, a water molecule, incorporated into the crystal of the chiral t-Boc-D -Ala-OH, alters in part that hydrogen-bonding scheme. In the two independent molecules of the unit cell of the optically active alanine derivative, as in that of the racemic derivative: (i) the conformation of the —CONH group is trans, also a new observation for a N-urethanyl-α-amino acid, and (ii) the overall conformation is quasi-extended. These findings exclude the occurrence of an oxy-C₇ peptide conformation. In solvents of high polarity, strongly solvated species predominate, as shown by ir absorption spectroscopy. In deuterochloroform nonassociated and associated species occur simultaneously. No differences were observed between the optically active and racemic derivatives. The type of self-association near saturation seems to differ, at least in part, from that found in the anhydrous racemic compound in the crystal state.     

Crystal structures of dihydroxyacetone and its derivatives

The crystal and molecular structures of three crystalline forms of the dihydroxyacetone dimer, C6H12O6, DHA-dimer: alpha (1a), beta (1b), and gamma (1c), the hydrated calcium chloride complex of dihydroxyacetone monomer, CaCl2(C3H6O3)(2) x H2O, CaCl2(DHA)2 x H2O (2a), the tetrahydrated calcium chloride complex of dihydroxyacetone monomer, CaCl2(C3H6O3) x 4H2O, CaCl2(DHA) x 4H2O (2b), the dihydroxyacetone monomer, C3H6O3, DHA (2c), and dihydroxyacetone dimethyl acetal, C5H12O4, (MeO)2DHA (3) are described. Compounds 1a and 2b crystallize in the triclinic system, and 1b,c, 2a,c, and 3 are monoclinic. Molecules of all forms of dihydroxyacetone dimer 1a,b, and 1c are the trans isomers, with the 1,4-dioxane ring in the chair conformation and the hydroxyl and hydroxymethyl groups in axial and equatorial dispositions, respectively. The Ca2+ ions in 2a and 2b are bridged by the carbonyl O atoms from two symmetry-related DHA molecules to form centrosymmetric dimers with Ca...Ca distance of 4.307(2)A in 2a and 4.330(2) and 4.305(2)A in two crystallographically independent dimers in 2b. DHA molecules coordinate to the Ca2+ ions by hydroxyl and carbonyl oxygen atoms. The eight-coordinate polyhedra of Ca2+ are completed by water molecule and Cl- ion in 2a and by four water molecules in 2b. The dihydroxyacetone molecules in 2a,b, and 2c are in an extended conformation, with both hydroxyl groups being synperiplanar (sp) to the carbonyl O atom. All hydroxyl groups in 2c (along with water molecules in 2a and 2b) are involved as donors in medium strong and weak intermolecular O-H...O hydrogen bonding. Some of them, as well as carbonyl O atoms or Cl- ions in 2a and 2b, act as acceptors in C-H...O (and C-H...Cl) hydrogen interactions.     

Conformational stability of antamanide and analogs. Crystal structure of perhydrosymmetric antamanide, cyclic (-Val-Pro-Pro-Cha-Cha-Val-Pro-Pro-Cha-Cha-)

The synthetic perhydrogenated symmetric analog of the cyclic decapeptide antamanide is biologically inactive, although the conformation of the molecule and the crystal packing are very similar to that of the active symmetric analog of antamanide. In fact, the same conformation for the molecule has now been found in six polymorphs of uncomplexed antamanide and its analogs. The differences between the active and inactive antamanide analogs are displayed dramatically in the conformations of their metal ion (Na+ or Li+) complexes, thus suggesting strongly that for physiological activity antamanide is not in the conformation assumed by the uncomplexed molecule, but rather in the conformation assumed by the complexed state of natural antamanide. The present structure crystallizes in space group P2(1)2(1)2(1) with a = 20.515(14) A, b = 21.316(16) A, c = 17.128(16) A and four peptide molecules in the unit cell. There are three cocrystallized water molecules at full occupancy intrinsic to the peptide, and several more water molecules or other solvent molecules at partial occupancy. The formula of the peptide is C66H106N10O10.4-H2O.2X.     

Spectroscopic rationalization of the separation abilities of decaproline chiral selector in dichloromethane-isopropanol solvent mixture

A chiral column, with decaproline as the chiral selector, has broad chiral selectivity. To understand the separation mechanism of this chiral column, multiple spectroscopic techniques, including optical rotation, electronic circular dichroism, infrared absorption and vibrational circular dichroism, have been used here to study the conformation of the decaproline oligomer in isopropanol(IPA)/dichloromethane(DCM) mixtures. These studies indicate that decaproline oligomer adopts polyproline II conformation in IPA/DCM solvent system (0% IPA approximately 100% IPA). Hydrogen bonding interactions between C=O groups of decaproline and IPA molecules increase as the content of IPA in the solvent mixture increases up to 60% and become less significant from then onwards. These spectroscopic observations are found to have a good correlation with the enantiomeric separation of racemic 2,2,2-trifluoro-1-[10-(2,2,2-trifluoro-1-hydroxy-ethyl-anthracen-9-yl]-ethanol by the decaproline column.     

Conformation and packing properties of membrane lipids: the crystal structure of sodium dimyristoylphosphatidylglycerol

The conformation and molecular packing of sodium 1,2-dimyristoyl-sn-glycero-phospho-rac-glycerol (DMPG) have been determined by single crystal analysis (R = 0.098). The lipid crystallizes in the monoclinic spacegroup P2(1) with the unit cell dimensions a = 10.4, b = 8.5, c = 45.5 A and beta = 95.2 degrees. There are two independent molecules (A and B) in the asymmetric unit which with respect to configuration and conformation of their glycerol headgroup are mirror images. The molecules pack tail to tail in a bilayer structure. The phosphoglycerol headgroups have a layer-parallel orientation giving the molecules an L-shape. At the bilayer surface the (-) phosphoglycerol groups are arranged in rows which are separated by rows of (+) sodium ions. Laterally the polar groups interact by an extensive network of hydrogen, ionic and coordination bonds. The packing cross-section per molecule is 44.0 A2. The hydrocarbon chains are tilted (29 degrees) and have opposite inclination in the two bilayer halves. In the chain matrix the chain planes are arranged according to a so far unknown hybride packing mode which combines the features of T parallel and O perpendicular subcells. The two fatty acid substituted glycerol oxygens have mutually a - synclinal rather than the more common + synclinal conformation. The conformation of the diacylglycerol part of molecule A and B is distinguished by an axial displacement of the two hydrocarbon chains by four methylene units. This results in a reorientation of the glycerol back bone and a change in the conformation and stacking of the hydrocarbon chains. In molecule A the beta-chain is straight and the gamma-chain is bent while in molecule B the chain conformation is reversed.     

Variability in the backbone conformation of cyclic pentapeptides. Crystal structure of cyclic(Gly-L-Pro-D-Phe-Gly-L-Ala)

All the peptide bonds in cyclic(Gly-L-Pro-D-Phe-Gly-L-Ala) are in the trans conformation; however, the peptide bond C'5-N1 is twisted by 19 degrees from planarity (omega 5 = -161 degrees). A Type II beta-turn encompasses the L-Pro-D-Phe residues. Carbonyl oxygens O2, O4 and O5 are directed to the same side of the average plane through the backbone ring and they form hydrogen bonds with N3, N5 and N1, respectively, in adjacent molecules in a stacked column where the adjacent molecules are related by one translational unit. The conformation of the backbone is different from that established in other molecules with the DLDDL chirality sequence. The P21 cell contains two molecules of C21H26N5O5 with a = 4.836(2) A, b = 18.346(8) A, c = 12.464(5) A and beta = 100.05(4) degrees. The R factor for 1382 data with [F0[ greater than 1 sigma is 7.0%.     

Electron microscopy of the conformational changes of alpha 2-macroglobulin from human plasma

High resolution electron microscopy reveals that fully active alpha 2-macroglobulin (α2M) from fresh human plasma presents a very characteristic tetrameric structure. This native conformation of the α2M molecule is described here for the first time, along with its various orientations in negatively stained preparations. Although the native form is sensitive to inactivation, glutaraldehyde fixation is not necessary for its observation except when ammonium salts are used. The tetrameric structure of α2M undergoes a drastic conformational change when the protein is treated either with trypsin, thrombin or methylamine, as evidenced by the appearance of the typical)+(structure already described in the literature. The various aspects of this second conformation correspond to different orientations of the molecules in the stain film, and depend upon the nature of the support.     

Three different types of chirality-driven crystallization within the series of uniformly substituted phenyl glycerol ethers

Seven chiral arylglycerol ethers 2-R-C(6)H(4)-O-CH(2)CH(OH)CH(2)OH (R = H, Me, Et, Allyl, n-Pr, i-Pr, tert-Bu) were synthesized in racemic and scalemic form. The IR spectra, melting points, and enthalpies of fusion for racemic and scalemic samples of every species were measured, the entropies of enantiomers mixing in the liquid state and Gibbs free energies of a racemic compound formation were derived and binary phase diagrams were reconstructed for the whole family. Solid racemic compounds stabilities were ranked for the four substances. Spontaneous resolution was established for the registered chiral drug mephenesin and its ethyl analogue. Metastable anomalous conglomerate, forming crystals having three independent R* and one independent S* molecules in the unit cell, is formed during solution crystallization of tert-butyl derivative; metastable phase transforms slowly into traditional racemic conglomerate.     

Molecular structures and hydrogen-bond networks in crystals of synthetic 1-D-galactosamide bolaamphiphiles

The crystal structures of synthetic 1-galactosamide bolaamphiphiles, N,N'-bis(beta-D-galactopyranosyl)decane-1,10-dicarboxamide (1) and N,N'-bis(beta-D-galactopyranosyl)dodecane-1,12-dicarboxamide (2), were determined by single-crystal X-ray analysis. The space groups are P21, Z = 2 with cell dimensions: a = 13.624(2), b = 4.832(3), c = 21.178(3) Angstroms, beta = 98.57(1) degrees for 1; a = 13.521(2), b = 4.838(1), c = 23.706(2) Angstroms, beta = 104.945(10) degrees for 2. The galactopyranosyl rings of 1 and 2 are in a 4C1 chair conformation. The bolaamphiphile molecules are arranged in a layered structure for 1 and 2, with the alkylene chains packed parallel all over the layers. The hydroxyl groups of the galactopyranosyl rings in 1 and 2 form identical three-dimensional hydrogen-bond networks. The connecting decamethylene spacer of 1 has a kink conformation, while the dodecamethylene chain of 2 an all-trans zigzag conformation.     

Synthesis, crystal structure and molecular conformation of the tBuCO-D,L-Ala-delta Z-Phe-NHiPr alpha,beta-unsaturated dipeptide

The crystal structure of the tBuCO-D,L-Ala-delta Z-Phe-NHiPr dipeptide has been solved by X-ray diffraction. The peptide crystallizes in monoclinic space group P2(1)/c with a = 13.445 (3) A, b = 35.088 (4) A, c = 14.755 (3) A, beta = 116.73 (1) degree, Z = 12 and dc = 1.151 g.cm-3. The three independent molecules per asymmetric unit accommodate a beta II-folded conformation, but only one of them contains the typical i + 3----i interaction characterizing a beta-turn. In the other two molecules, the N...O distance exceeds 3.2 A, a value generally considered the upper limit for hydrogen bonds in peptides. In solution, the beta II-turn conformation is largely predominant.     

Lipase-catalyzed kinetic resolutions of racemic β- and γ-thiolactones

Several racemic β- and γ-thiolactones were synthesized and kinetic resolutions of them were executed using lipases. While a lipase from Pseudomonas cepacia (PCL) showed the highest enantioselectivity for (S)-form (>99% ee_S at 53% conversion, E > 100) in the kinetic resolution of racemic -methyl-β-propiothiolactone (rac-MPTL), it showed no hydrolysis activity in the kinetic resolution of -benzyl--methyl-β-propiothiolactone (rac-BMPTL), suggesting that the changes in the size of alkyl group from rac-MPTL to rac-BMPTL leads to lower hydrolysis activity and enantioselectivity. In contrast, racemic γ-butyrothiolactones were hydrolyzed by several lipases with low enantioselectivity, whereas a lipase from Candida antarctica (CAL) showed moderate enantioselectivity for (S)-form (>99% ee_S at 76% conversion, E = 11) in the kinetic resolution of racemic -methyl-γ-butyrothiolactone (rac-MBTL). Computer-aided molecular modeling was also performed to investigate the enantioselectivites and activities of PCL toward β-propiothiolactones. The computer modeling results suggest that the alkyl side chains of β-propiothiolactones and γ-butyrothiolactones interact with amino acid residues around hydrophobic crevice, which affects the activity of PCL.     

Crystal structure of cadaverine dihydrochloride monohydrate.

The structure of cadaverine dihydrochloride monohydrate has been determined by X-ray crystallography with the following features: NH3+ (CH2)5NH3+.2Cl-.H2O, formula weight 191.1, monoclinic, P2, a = 11.814(2)A, b = 4.517(2)A, c = 20.370(3)A, beta = 106.56 degrees (1): V = 1041.9(2)A3; lambda = 1.541A; mu = 53.41; T = 296 degrees; Z = 4, Dx = 1.218 g.cm-3, R = 0.101 for 1383 observed reflections. The crystal is highly pseudo-symmetric with 2 molecules of cadaverine, 4 chloride ions and 2 partially disordered water molecules present in the asymmetric unit. Though both the cadaverine molecules in the asymmetric unit have an all trans conformation, the carbon backbones are slightly bent. Between the concave surfaces of two bent cadaverine molecules exists water channels all along the short b axis. The water molecules present in the channels are partially disordered.     

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 C3'exo/C4'endo (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.     

Crystal and molecular structure of Boc-D-Ala-delta Phe-Gly-delta Phe- D-Ala-OMe: a 3 10-helical dehydropeptide

The crystal and molecular structure of the pentapeptide Boc-D-Ala-delta Phe-Gly-delta Phe-D-Ala-OMe, containing two dehydrophenylalanine residues, was determined by x-ray diffraction. The molecule crystallizes in the orthorombic P2(1)2(1)2(1) space group, with a = 10.439(3), b = 15.319(3) and c = 21.099(4) A. In the solid state, the conformation of the pentapeptide is characterized by the presence of two type III' beta-turns. Thus the peptide assumes a left-handed 3(10-helical conformation, the left sense being due to the D configuration of the alanine residues. The two unsaturated residues are located in the (i + 1) position of the first beta-turn and in the (i + 2) position of the second beta-turn, respectively. In the crystal, the helical molecules are linked head to tail by hydrogen bonds. Lateral hydrogen bonds are also formed between molecules related by a twofold screw symmetry. This gives rise to a typical mode of packing characterized by infinite helical "chains,' similar to the packing found in other oligopeptides that adopt a 3(10)-helical structure.     

Crystal structure of the alpha, beta, gamma-tridentate manganese complex of adenosine 5'-triphosphate cocrystallized with 2,2'-dipyridylamine

The 1:1:1 complex of Mn2+, ATP, and 2,2'-dipyridylamine (DPA) crystallizes as Mn-(HATP)2.Mn(H2O)6.(HDPA)2.12H2O in the orthorhombic space group C222(1) with unit cell dimensions a = 10.234 (3) A, b = 22.699 (3) A, and c = 31.351 (4) A. The structure was solved by the multisolution technique and refined by the least-squares method to a final R index of 0.072 using 3516 intensities. The structure is composed of two ATP molecules sharing a common manganese atom. The metal exhibits alpha, beta, gamma coordination to the triphosphate chains of two dyad-related ATP molecules, resulting in a hexacoordinated Mn2+ ion surrounded by six phosphate groups. The metal to oxygen distances are 2.205 (6), 2.156 (4), and 2.144 (5) A for the alpha-, beta-, and gamma-phosphate groups, respectively. No metal-base interactions are observed. There is a second hexaaqua-coordinated Mn2+ ion that is also located on a dyad axis. The hydrated manganese ions sandwich the phosphate-coordinated manganese ions in the crystal with a metal-metal distance of 5.322 A. The ATP molecule is protonated on the N(1) site of the adenine base and exhibits the anti conformation (chi = 66.0 degrees). The ribofuranose ring is in the 2/3 T conformation with pseudorotation parameters P = 179 (1) degrees and tau m = 34.1 (6) degrees. The adenine bases form hydrogen-bonded self-pairs across a crystallographic dyad axis and stack with both DPA molecules to form a column along the dyad. The structure of the metal-ATP complex provides information about the possible metal coordination, conformation, and environment of the nucleoside triphosphate substrate in the enzyme.