Crystal and molecular structures of new enantiopure quinuclidines

X-ray crystal structure analysis was performed on single crystals of two diastereomeric enantiopure quinuclidines, (3R,8R)-3-vinyl-8-hydroxymethyl-quinuclidine (quincoridine, QCD) and (3R,8S)-3-vinyl-8-hydroxymethyl-quinuclidine (quincorine, QCI) as their salts with tartaric and p-toluenesulphonate anions, respectively. The molecules of these quinuclidine derivatives are considered here as fragments of the Cinchona alkaloids, quinidine and quinine. A comparison of the conformational features of QCD, QCI, and Cinchona alkaloids in the crystalline state shows that the molecular geometry of the title compounds is similar to that of threo-alkaloids (e.g., R,R isomer of epicinchonine) rather than to quinidine and quinine. The packing of the molecules in both structures is dominated by intermolecular hydrogen bonds.     

Crystal and molecular structures of trichloro-cobalt(II) complexes of epiquinine, epiquinidine, and epidihydrocinchonine

Cinchona alkaloids are very well known antimalarials but the mechanism of their biological action still remains to be elucidated. The structural studies of active erythro and inactive threo alkaloid complexes are an important step to this aim. In this paper results of crystal structure analysis of three cobalt complexes of threo alkaloids are presented: (epiquininium)trichlorocobalt(II) (EpiQnCoCl3), (epiquinidinium)trichlorocobalt(II) (EpiQdCoCl3) and (epidihydrocinchoninium)trichlorocobalt(II) (EpiCnCoCl3). The complexes are zwitterions in which trichlorocobalt substituents are coordinated to quinoline nitrogen atoms and quinuclidine nitrogen atoms are protonated. EpiQnCoCl3 adopts uncommon conformation with quinoline moiety oriented in the opposite direction in comparison to the analogous uncomplexed alkaloid. The packing in the crystal structures is determined mainly by the hydrogen bonds, in which the chlorine atoms of substituents and solvent molecules contribute. Atoms participating in hydrogen bonds in EpiQnCoCl3 and EpiQdCoCl3 form large rings, while in EpiCnCoCl3 only chains are present. Solvent molecules are very important for the packing mode. In contrast to most erythro alkaloids, the hydroxyl oxygen atom in the title complexes forms weak or not well defined hydrogen bonds. The contribution of very weak intramolecular interactions N1--H1...O12 cannot be excluded. Such "trace" interactions can be considered a relic of the unprotonated status of an epi alkaloid.     

Enantioselective anion exchangers based on cinchona alkaloid‐derived carbamates: Influence of C8/C9 stereochemistry on chiral recognition

Four diastereomeric chiral stationary phases (CSPs) based on quinine, quinidine, epiquinine, and epiquinidine tert‐butyl carbamate selectors were synthesized and evaluated under ion exchange HPLC conditions with a set of racemic N‐acylated and N‐oxycarbonylated α‐amino acids as selectands. The enantioseparation potential of quinine‐ and quinidine‐derived CSPs proved to be far superior to that of their C₉‐epimeric congeners. The absolute configuration of C₉ stereogenic center of the cinchonan backbone of these selectors was identified as the structural feature controlling the elution order. Guided by an X‐ray structure of a most favorable selector–selectand complex and the observed chromatographic enantioseparation data, a chiral recognition model was advanced. The contributions of ion‐pairing, π–π donor–acceptor, hydrogen bonding and steric interactions were established as crucial factors. Chirality 11:522–528, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis and C(2) -symmetric structure of a cyclotetrapeptide composed of anthranilic acid and leucine

A chiral cyclotetrapeptide (1) was synthesized from 2-nitrobenzoic acid and leucine. A single-crystal X-ray of the compound revealed a C(2) -symmetric bowl-shaped structure. The cyclic compound had a unique hydrogen-bonding network composed of three-centered hydrogen bonds and bifurcated hydrogen bonds between NH and CO of anthranilic residue. The NMR spectra and molecular modeling of 1 also suggested the chiral bowl structure.     

Enantiomerically pure quaternary ammonium salts with a chiral alkyl chain N(CH3)(n-C3H7)2(sec-C4H9)I: synthesis and physical studies

A pair of enantiomerically pure quaternary ammonium salts with a chiral side chain, methyl-(R)-(1-methylpropyl)di(n-propyl)ammonium iodide 1 and methyl-(S)-(1-methylpropyl)di(n-propyl)ammonium iodide 2, and the related racemate, methyl-(rac)-(1-methylpropyl)di(n-propyl)ammonium iodide 3, were synthesized through a reductive alkylation procedure, starting from enantiomerically pure and, also, racemic forms of (rac)-(1-methylpropyl)amine. A spectroscopic chiroptical signature in solution was provided by the Raman optical activity spectra of compounds 1 and 2. The crystallographic structures of 1, 2, and 3 were examined by single crystal X-ray diffraction. 1 crystallizes in the tetragonal space group P4(3)2(1)2 (no. 96), a = b = 12.826 (2) A, c = 17.730 (2) A, V = 2916.9 (5) A(3), Z = 8, Flack coefficient 0.04 (2). 2 crystallizes in the tetragonal space group P4(1)2(1)2 (no. 92), a = b = 12.842 (1) A, c = 17.749 (2) A, V = 2927.0 (5) A(3), Z = 8, Flack coefficient 0.05 (2). The crystal structures and space groups for 1 and 2 are enantiomorphs and the crystallographic investigation confirmed the absolute configuration of the stereocenter in both compounds. 3 crystallizes in the monoclinic space group P2(1)/n(no. 14), a = 8.178 (1) A, b = 14.309 (2) A, c = 12.328 (2) A, beta = 96.811 (6) degrees, V = 1432.4 (2) A(3), Z = 4.     

Synthesis,density functional theory calculations and luminescence of lanthanide complexes with 2,6‐bis[(3‐methoxybenzylidene)hydrazinocarbonyl] pyridine Schiff base ligand

A pyridine‐diacylhydrazone Schiff base ligand, L = 2,6‐bis[(3‐methoxy benzylidene)hydrazinocarbonyl]pyridine was prepared and characterized by single crystal X‐ray diffraction. Lanthanide complexes, Ln–L, {[LnL(NO₃)₂]NO₃.xH₂O (Ln = La, Pr, Nd, Sm, Eu, Gd, Tb, Dy and Er)} were prepared and characterized by elemental analysis, molar conductance, thermal analysis (TGA/DTGA), mass spectrometry (MS), Fourier transform infra‐red (FT‐IR) and nuclear magnetic resonance (NMR) spectroscopy. Ln–L complexes are isostructural with four binding sites provided by two nitro groups along with four coordination sites for L. Density functional theory (DFT) calculations on L and its cationic [LnL(NO₃)₂]⁺ complexes were carried out at the B3LYP/6–31G(d) level of theory. The FT‐IR vibrational wavenumbers were computed and compared with the experimentally values. The luminescence investigations of L and Ln–L indicated that Tb–L and Eu–L complexes showed the characteristic luminescence of Tb(III) and Eu(III) ions. Ln–L complexes show higher antioxidant activity than the parent L ligand.     

Solvent effects of N‐nitroso,N‐(2‐chloroethyl), N′,N′‐dibenzylsulfamid and its copper(II) and cobalt(II) complexes: fluorescence studies

The structure of N‐nitroso, N‐(2‐chloroethyl), N′,N′‐dibenzylsulfamid (CENS) was established by X‐ray crystallography. The atomic coordinates, factors of isotropic thermal agitation, bond lengths and valence angles were determined. The solvent effects on the electronic absorption and fluorescence spectra of CENS were investigated at room temperature. The effects of solvent polarity and of hydrogen bonding were interpreted by means of linear solvation energy relationships (LSERs). Multiple linear regression analysis indicated that the hydrogen donation properties of the solvent play an important role in determining the position of the absorption maximum, while the classical polarity of the medium is the only dominating parameter in determining the emission maximum and the Stokes' shift. Complexation of the investigated compound by two different transition metal ions was studied. Fluorescence measurements show that fluorescence quenching by cobalt(II) is more important than that by copper(II). This phenomenon can be attributed to good stereo‐structural matching between the electronic configuration of the Co²⁺ ion and the active site distribution of CENS in aqueous solution. Copyright © 2012 John Wiley & Sons, Ltd.     

Crystal structure of yeast hexokinase PI in complex with glucose: A classical "induced fit" example revised

Hexokinase is the first enzyme in the glycolytic pathway that catalyzes the transfer of a phosphoryl group from ATP to glucose to form glucose-6-phosphate and ADP. Two yeast hexokinase isozymes are known, namely PI and PII. Here we redetermined the crystal structure of yeast hexokinase PI from Saccharomyces cerevisiae as a complex with its substrate, glucose, and refined it at 2.95 A resolution. Comparison of the holo-PI yeast hexokinase and apo-hexokinase structures shows in detail the rigid body domain closure and specific loop movements as glucose binds and sheds more light on structural basis of the "induced fit" mechanism of reaction in the HK enzymatic action. We also performed statistical coupling analysis of the hexokinase family, which reveals two co-evolved continuous clusters of amino acid residues and shows that the evolutionary coupled amino acid residues are mostly confined to the active site and the hinge region, further supporting the importance of these parts of the protein for the enzymatic catalysis.     

One and two dimensional 1H and 13C high resolution NMR investigation of lariat ethers and their alkali metal ionic complexes: a more tangible evidence for the presence of less common C-H***O hydrogen bonds

The possible existence of less common hydrogen bonds in three lariat ethers and their alkali-metal ionic complexes have been investigated with one- and two-dimensional (1D and 2D) proton and carbon-13 high resolution liquid state NMR spectroscopy. The occurrence of hydrogen-bonding induced by the addition of metal ions has been identified with the observation of indirect dipolar coupling between the coupling partners involved in the hydrogen-bonding. The addition of metal ions, moreover, causes appreciable change of chemical shift of several protons and carbons. The chemical shift change depends on the ion radius, larger ions causing smaller change. Moreover, the change of chemical shift is in coincidence with the occurrence of hydrogen-bonding. The values of the coupling constants have been obtained for each of these hydrogen bonds and were used for evaluating the hydrogen-bond strength. An intriguing and surprising observation is that a C-H***O hydrogen bond identified in solution by this work was not found in the previous study with X-ray diffraction or other methods.     

Productive and nonproductive binding to ribonuclease A: X-ray structure of two complexes with uridylyl(2',5')guanosine

Guanine-containing mono- and dinucleotides bind to the active site of ribonuclease A in a nonproductive mode (retro-binding) (Aguilar CF, Thomas PJ, Mills A, Moss DS, Palmer RA. 1992. J Mol Biol 224:265-267). Guanine binds to the highly specific pyrimidine site by forming hydrogen bonds with Thr45 and with the sulfate anion located in the P1 site. To investigate the influence of the anion present in the P1 site on retro-binding, we determined the structure of two new complexes of RNase A with uridylyl(2',5')guanosine obtained by soaking two different forms of pre-grown RNase A crystals. In one case, RNase A was crystallized without removing the sulfate anion strongly bound to the active site; in the other, the protein was first equilibrated with a basic solution to displace the anion from the P1 site. The X-ray structures of the complexes with and without sulfate in P1 were refined using diffraction data up to 1.8 A (R-factor 0.192) and 2.0 A (R-factor 0.178), respectively. The binding mode of the substrate analogue to the protein differs markedly in the two complexes. When the sulfate is located in P1, we observe retro-binding; whereas when the anion is removed from the active site, the uridine is productively bound at the B1 site. In the productive complex, the electron density is very well defined for the uridine moiety, whereas the downstream guanine is disordered. This finding indicates that the interactions of guanine in the B2 site are rather weak and that this site is essentially adenine preferring. In this crystal form, there are two molecules per asymmetric unit, and due to crystal packing, only the active site of one molecule is accessible to the ligand. Thus, in the same crystal we have a ligand-bound and a ligand-free RNase A molecule. The comparison of these two structures furnishes a detailed and reliable picture of the structural alterations induced by the binding of the substrate. These results provide structural information to support the hypotheses on the role of RNase A active site residues that have recently emerged from site-directed mutagenesis studies.     

Novel approach for the introduction of a C-1 oxygenated group on the decalin skeleton: first asymmetric total synthesis of 1S,6S-dihydroxy-eudesm-3-ene

This paper describes a novel approach for the introduction of a C-1 hydroxyl on the decalin ring system, starting from (-)-carvone. Utilizing the substrate-controlled Mukaiyama aldol reaction and alkaline cyclization as key steps, the C-1 oxygenated decalin eudesmane skeleton 2' and its four isomers were synthesized efficiently. Furthermore, X-ray structural analysis showed that the claimed structure for the natural product is incorrect.     

7Li-NMR and FTIR studies of lithium, potassium, rubidium, and cesium complexes with ionophore lasalocid in solution

Lasalocid metal salts were combined with 1 : 1 lithium and 2:2 potassium, rubidium, and cesium to form complexes. The nature of the lasolocid salt complexes was studied in a solid and chloroform by FTIR spectroscopy in the middle and far IR regions. The process of the complexation of lithium was also studied by (7)Li-NMR. In chloroform a 1 : 1 complex of lasalocid and Li(+) ions was formed. Continuous absorption was observed in the far FTIR spectrum of this complex. It indicated large Li(+) polarizability, which was due to fast fluctuations of the Li(+) ions in the multiminima potentials, in the monomeric structure. In the lasalocid salt with the other monovalent cations (K(+), Rb(+), Cs(+)) 2:2 complexes were formed in which the cations showed cation polarizability, which strongly depended on the mass and the radius of the cations.     

Guest-dependent conformation of 18-crown-6 tetracarboxylic acid: relation to chiral separation of racemic amino acids

(+)-18-crown-6 tetracarboxylic acid (18C6H(4)) has been used as a chiral selector for various amines and amino acids. To further clarify the structural scaffold of 18C6H(4) for chiral separation, single crystal X-ray analysis of its glycine(+) (1), H3O+ (2), H5O2+ (3), NH4+ (4), and 2CH3NH3+ (5) complexes was performed and the guest-dependent conformation of 18C6H(4) was investigated. The crown ether ring of 18C6H4 in 3, 4, and 5 took a symmetrical C2 or C2-like conformation, whereas that in 1 and 2 took an asymmetric C1 conformation, which is commonly observed in complexes with various optically active amino acids. The overall survey of the present and related complexes suggests that the molecular conformation of 18C6H4 is freely changeable within an allowable range, depending on the molecular shape and interaction mode with the cationic guest. On the basis of the present results, we propose the allowable conformational variation of 18C6H4 and a possible transition pathway from its primary conformation to the conformation suitable for chiral separation of racemic amines and amino acids.     

Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structural features of four Vlambda6 proteins

Primary (AL) amyloidosis results from the pathologic deposition of monoclonal light chains as amyloid fibrils. Studies of recombinant-derived variable region (VL) fragments of these proteins have shown an inverse relationship between thermodynamic stability and fibrillogenic potential. Further, ionic interactions within the VL domain were predicted to influence the kinetics of light chain fibrillogenicity, as evidenced from our analyses of a relatively stable Vlambda6 protein (Jto) with a long range electrostatic interaction between Asp and Arg side chains at position 29 and 68, respectively, and an unstable, highly fibrillogenic Vlambda6 protein (Wil) that had neutral amino acids at these locations. To test this hypothesis, we have generated two Jto-related mutants designed to disrupt the interaction between Asp 29 and Arg 68 (JtoD29A and JtoR68S). Although the thermodynamic stabilities of unfolding for these two molecules were identical, they exhibited very different kinetics of fibril formation: the rate of JtoD29A fibrillogenesis was slow and comparable to the parent molecule, whereas that of JtoR68S was significantly faster. High-resolution X-ray diffraction analyses of crystals prepared from the two mutants having the same space group and unit cell dimensions revealed no significant main-chain conformational changes. However, several notable side-chain alterations were observed in JtoR68S, as compared with JtoD29A, that resulted in the solvent exposure of a greater hydrophobic surface and modifications in the electrostatic potential surface. We posit that these differences contributed to the enhanced fibrillogenic potential of the Arg 68 mutant, since both Jto mutants lacked the intrachain ionic interaction and were equivalently unstable. The information gleaned from our studies has provided insight into structural parameters that in addition to overall thermodynamic stability, contribute to the fibril forming propensity of immunoglobulin light chains.     

Structure and dynamics of gamma-SNAP: insight into flexibility of proteins from the SNAP family

Soluble N-ethylmaleimide-sensitive factor attachment protein gamma (gamma-SNAP) is a member of an eukaryotic protein family involved in intracellular membrane trafficking. The X-ray structure of Brachydanio rerio gamma-SNAP was determined to 2.6 A and revealed an all-helical protein comprised of an extended twisted-sheet of helical hairpins with a helical-bundle domain on its carboxy-terminal end. Structural and conformational differences between multiple observed gamma-SNAP molecules and Sec17, a SNAP family protein from yeast, are analyzed. Conformational variation in gamma-SNAP molecules is matched with great precision by the two lowest frequency normal modes of the structure. Comparison of the lowest-frequency modes from gamma-SNAP and Sec17 indicated that the structures share preferred directions of flexibility, corresponding to bending and twisting of the twisted sheet motif. We discuss possible consequences related to the flexibility of the SNAP proteins for the mechanism of the 20S complex disassembly during the SNAP receptors recycling.     

Multinuclear NMR and FTIR studies of new polyoxaalkyl esters of lasalocid and their complexes with lithium and sodium cations

Three new polyoxaalkyl esters of lasalocid are synthesized. Their ability to form complexes with Li(+) and Na(+) cations is studied using multinuclear NMR methods, FTIR spectroscopy in the middle and far IR regions, and mass spectrometry. It is found that lasalocid esters form only 1:1 complexes with the metal cations. The results of the NMR study in pyridine show that the polyoxaalkyl chain of the ester does not influence the complex formation of the lasalocid part of the esters. The reason for this is the competition of the pyridine molecules in the complexation process of metal cations. In chloroform the properties of the complex formation have changed and the oxaalkyl chain plays an important role within the complexation process, as demonstrated by the dependence of the respective continuous absorptions in the far IR region on the length of the oxaalkyl chain (i.e., on the number of the oxygen atoms in the chain). The modifications of the lasalocid molecule influences the complexation of the metal cation and probably the interactions with the membrane. An increase in antibiotic activity is found as a consequence of these changed interactions.