Chemical-structural properties of tetracycline derivatives. 1. Molecular structure and conformation of the free base derivatives.
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Chemical Phenomena↗
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Xanthan gum production under several operational conditions: molecular structure and rheological properties*
Xanthan gum production under several operational conditions has been studied. Temperature, initial nitrogen concentration and oxygen mass transfer rate have been changed and average molecular weight, pyruvilation and acetylation degree of xanthan produced have been measured in order to know the influence of these variables on the synthesised xanthan molecular structure. Also, xanthan gum solution viscosity has been measured, and rheological properties of the solutions have been related to molecular structure and operational conditions. The Casson model has been employed to describe the rheological behaviour. The parameter values of the Casson model, tau(0) and K(c), have been obtained for each polysaccharide synthesised under different operational conditions. Both pyruvilation and acetylation degrees and average molecular weight of xanthan increase with fermentation time at any operating conditions. Xanthan molecules with the highest average molecular weight have been obtained at 25 degrees C. Nevertheless, at this temperature acetate and pyruvate radical concentration are lowest. Nitrogen concentration in broth does not show any clear influence over xanthan average molecular weight, although with high nitrogen source concentration xanthan with low pyruvilation degree is produced.
Journal Article↗
Molecular structure of the water channel through aquaporin CHIP. The hourglass model.
Aquaporin channel-forming integral protein (CHIP) is the first characterized water channel protein (genome symbol AQP1), but the molecular structure of the aqueous pathway through CHIP remains undefined. The two halves of CHIP are sequence-related, and each has three bilayer-spanning domains with the motif asparagine-proline-alanine (NPA) at residues 76-78 (in cytoplasmic loop B) and 192-194 (in extracellular loop E). The NPA motifs are oriented 180 degrees to each other, and the second NPA is near cysteine 189, the known site where mercurials inhibit osmotic water permeability (Pf). When expressed in Xenopus oocytes, the double mutant A73C/C189S exhibited high, mercurial-sensitive Pf similar to wild-type CHIP. Conservative substitutions of slightly greater mass in or near NPA motifs in loop B or loop E in CHIP caused reduced Pf and failure of the protein to localize at the plasma membrane. Certain nonfunctional loop E mutants complemented the truncation mutant D237Z. Formation of mixed oligomers was demonstrated by velocity sedimentation, immunoprecipitation, and analysis of dimeric-CHIP polypeptides. Cellular distributions of individual mutants or complementing pairs of mutants were verified by plasma membrane isolation and confocal microscopy. An hourglass structural model is proposed in which a cytoplasmic chamber (loop B) connects within the membrane to an extracellular chamber (loop E) forming a single, narrow aqueous pathway through each of the CHIP subunits; subunit oligomerization may provide the vertical symmetry necessary for residence within the lipid bilayer.
Amino Acid Sequence↗
Molecular structure of lathyritol, a galactosylbornesitol from Lathyrus odoratus seeds, by NMR.
The molecular structure of galactosyl-D-(-)-bornesitol, a novel compound isolated from sweet pea seeds, was determined to be alpha-D-galactopyranosyl-(1-->3)-1-O-methyl-1D-myo-inositol by 1D and 2D NMR spectroscopy and is assigned the trivial name lathyritol.
Carbohydrate Sequence↗
Renin inhibitor: relationship between molecular structure and oral absorption.
Common problems in developing renin inhibitors are low solubility, insufficient oral absorption, and fast hepatic clearance. We focused on the molecular structure of renin inhibitors to overcome these problems. Cyclodextrins (CD) improved the low solubility of renin inhibitors, with beta-CD showing the best ability to dissolve renin inhibitors. The intestinal absorption of renin inhibitors varied with both their solubility and molecular structure. Coadministration of beta-CD improved the intestinal absorption of some renin inhibitors with low solubility as measured by transport into the mesenteric vein in the absorption experiment using the rat intestinal loop. Substitutions at both the N and C terminals was essential for absorption from the small intestine. A naphthyl group at the N-terminal further improved intestinal absorption. A carrier system appeared to be involved in the intestinal absorption of some renin inhibitors. N-methylation at the amide bond of thiazolylalanine suppressed the high hepatic clearance of one of the test compounds 18 which was well absorbed from the small intestine and it improved its oral bioavailability.
Animals↗
Animal DNA-dependent RNA polymerases. Purification and molecular structure of hen-oviduct and liver class-B RNA polymerases.
Hen ovidcut and liver class B RNA polymerases have been extensively purified and their molecular structure has been analysed. While only one enzyme B form (BIIb) was found in liver, three forms (BI, BIIa and BIIb) were resolved from oviduct. The molecular structures of the various class B RNA polymerase forms purified from hen oviduct and liver are identical to the corresponding forms previously purified from calf thymus and rat liver. At the present level of resolution the only difference lies in a slight difference in the charge of one subunit (SB2a) of enzyme form BIIa, when comparing the mammal and bird enzymes. It is unlikely that the absence of enzyme forms BI and BIIa in purified hen liver RNA polymerase B could be related to limited and specific proteolysis during the purification, since co-purification of oviduct and liver RNA polymerase B activities from a mixture of oviduct and liver nuclei does not affect the presence of either oviduct enzyme form BI or BIIa in the final purified mixture.
Amanitins↗
Serum levels of soluble Fas/APO-1 (CD95) and its molecular structure in patients with systemic lupus erythematosus (SLE) and other autoimmune diseases.
There are two major forms of the Fas molecule, membranous Fas and soluble Fas (sFas). To clarify the clinical significance of sFas in autoimmune diseases, we designed a sandwich ELISA to determine serum concentrations of sFas and its molecular structure, and we then analysed the correlation between levels of sFas and laboratory findings in patients with SLE and other autoimmune diseases. The levels of serum sFas were significantly higher in SLE patients than in subjects with other autoimmune diseases and in healthy donors, and the frequency of a positive serum sFas was much greater in SLE patients with high SLE disease activity index scores than in those with low scores. In addition, sFas-positive SLE patients showed a significant difference in various laboratory parameters from sFas-negative SLE patients. Serial measurements of serum sFas levels in SLE patients with active disease revealed that the elevated level of sFas dramatically decreased with improvement in clinical and laboratory findings, following corticosteroid therapy. We propose that the serum level of sFas can serve as an appropriate marker for evaluating SLE disease activity. Serum sFas is heterogeneous with respect to molecular structure, thus several mechanisms are involved in the generation of sFas.
Autoimmune Diseases↗
Calculating three-dimensional molecular structure from atom-atom distance information: cyclosporin A.
In recent years methods for deriving spatial molecular structure from atom-atom distance information have gained in importance due to the emergence of two-dimensional nuclear magnetic resonance (n.m.r) techniques, which make it possible to obtain such distance information for polypeptides, small proteins, sugars, and DNA fragments in solution. Distance geometry (DG) and restrained molecular dynamics (MD) refinement are applied to a cyclic polypeptide, the immunosuppressive drug cyclosporin A, and the results are compared. Two different procedures, DG followed by restrained MD, and straightforward restrained MD starting from the X-ray structure, both lead to a unique conformation that satisfies the 58 experimentally determined distance constraints. The results nicely show the relative merits of DG and restrained MD techniques for determining spatial molecular structure from distance information.
Cyclosporins↗
Do variations in molecular structure affect the clinical efficacy and safety of lipid-based amphotericin B preparations?
While amphotericin B is the drug of choice in the treatment of most fungal infections, systemic adverse reactions and dose-dependent nephrotoxicity associated with its use frequently render the conventional preparation of amphotericin unsuitable. A number of lipid-based formulations of amphotericin have been developed to overcome the limitations of the parent compound. These preparations, amphotericin B lipid complex (ABLC), amphotericin B colloid dispersion (ABCD) and liposomal amphotericin differ from one another significantly in their molecular structure. They are also considerably more expensive than the parent compound. Clinical data on their appropriate use are limited. This review looks at the differences in molecular structure of these preparations, and at the available clinical safety and efficacy data.
Amphotericin B↗
Elucidation of the molecular structure of hydrated vanadium oxide species by X-ray absorption spectroscopy: correlation between the V...V coordination number and distance and the point of zero charge of the support oxide.
The effect of the point of zero charge (PZC) of the support oxide (Al(2)O(3), Nb(2)O(5), SiO(2) and ZrO(2)) on the molecular structure of hydrated vanadium oxide species has been investigated with EXAFS spectroscopy for low-loaded vanadium oxide catalysts. It was found that the degree of clustering (i.e., the V[dot dot dot]V coordination number) and the V...V distance increase with decreasing PZC of the support oxide; i.e., Al(2)O(3) (8.7) < ZrO(2) (7) < Nb(2)O(5) (3.3) < SiO(2) (2). Upon hydration the silica-supported vanadium oxide exhibited a clear alteration in the position of the oxygen atoms surrounding the central vanadium atom and the number of oxygen atoms around vanadium increased to five. In contrast, only minor changes in the molecular structure were detected for the alumina-, niobia- and zirconia-supported vanadium oxide catalysts. Based on a detailed analysis of the EXAFS data a semi-quantitative distribution of vanadium oxide species present on the surface of the different support oxides can be obtained, which is in good agreement with earlier characterization studies primarily making use of Raman spectroscopy.
Absorption↗
A methodology for efficiently sampling the conformation space of molecular structures.
Motivated by recently developed computational techniques for studying protein flexibility, and their potential applications in docking, we propose an efficient method for sampling the conformational space of complex molecular structures. We focus on the loop closure problem, identified in the work of Thorpe and Lei (2004 Phil. Mag. 84 1323-31) as a primary bottleneck in the fast simulation of molecular motions. By modeling a molecular structure as a branching robot, we use an intuitive method in which the robot holds onto itself for maintaining loop constraints. New conformations are generated by applying random external forces, while internal, attractive forces pull the loops closed. Our implementation, tested on several model molecules with low number of degrees of freedom but many interconnected loops, gives promising results that show an almost four times speed-up on the benchmark cube-molecule of Thorpe and Lei.
Algorithms↗
Molecular structure of the solvated proton in isolated salts. Short, strong, low barrier (SSLB) H-bonds.
Large, inert, weakly basic carborane anions of the icosahedral type CHB(11)R(5)X(6)(-) (R = H, Me; X = Cl, Br) allow ready isolation and structural characterization of discrete salts of the solvated proton, [H(solvent)(x)][CHB(11)R(5)X(6)], (solvent = common O-atom donor). These oxonium ion Brønsted acids are convenient reagents for the tuned delivery of protons to organic solvents with a specified number of donor solvent molecules and with acidities leveled to those of the chosen donor solvent. They have greater thermal stability than the popular [H(OEt(2))(2)][BAr(F)] acids based on fluorinated tetraphenylborate counterions because carborane anions can sustain much higher levels of acidity. When organic O-atom donors such as diethyl ether, tetrahydrofuran, benzophenone, and nitrobenzene are involved, the coordination number of the proton (x) in [H(solvent)(x)()](+) is two. A mixed species involving the [H(H(2)O)(diethyl ether)](+) ion has also been isolated. These solid-state structures provide expectations for the predominant molecular structures of solvated protons in solution and take into account that water is an inevitable impurity in organic solvents. The O.O distances are all short, lying within the range from 2.35 to 2.48 A. They are consistent with strong, linear O.H.O hydrogen bonding. Density functional theory calculations indicate that all H(solvent)(2)(+) cations have low barriers to movement of the proton within an interval along the O.H.O trajectory, i.e., they are examples of so-called SSLB H-bonds (short, strong, low-barrier). Unusually broadened IR bands, diagnostic of SSLB H-bonds, are observed in these H(solvent)(2)(+) cations.
Anions↗
Determining molecular structures and conformations directly from electron diffraction using a genetic algorithm.
A global optimization strategy, based upon application of a genetic algorithm (GA), is demonstrated as an approach for determining the structures of molecules possessing significant conformational flexibility directly from gas-phase electron diffraction data. In contrast to the common approach to molecular structure determination, based on trial-and-error assessment of structures available from quantum chemical calculations, the GA approach described here does not require expensive quantum mechanical calculations or manual searching of the potential energy surface of the sample molecule, relying instead upon simple comparison between the experimental and calculated diffraction pattern derived from a proposed trial molecular structure. Structures as complex as all-trans retinal and p-coumaric acid, both important chromophores in photosensing processes, may be determined by this approach. In the examples presented here, we find that the GA approach can determine the correct conformation of a flexible molecule described by 11 independent torsion angles. We also demonstrate applications to samples comprising a mixture of two distinct molecular conformations. With these results we conclude that applications of this approach are very promising in elucidating the structures of large molecules directly from electron diffraction data.
Journal Article↗
An hypothesis of the molecular structure of the dopamine receptor.
Neurotensin has psychopharmacological properties similar to dopamine receptor blocking drugs. A Chou and Fasman analysis of the primary sequence suggests that the sequence 1-6 forms an alpha-helix broken by pro (7) and 9-12 forms a beta-turn. This allows the peptide molecule to form an amphoteric structure with, on one side, the evenly space array - p glu - glu - arg - arg - ( delta- - + +) which is self-complementary. Thus, two molecules of neurotensin placed head to tail can form a Kusnetsov-Ghokov grid with four cross-links (p glu and glu to arg - arg) x 2. The walls of a shadow potential receptor cup are formed by asn(5), pro(7), ile(12) and pro(10) on each side. CPK model building experiments indicate that this structure is complementary to a wide range of dopamine agonists and antagonists. Therefore, the hypothesis is presented that neurotensin may mimic part of the DA receptor protein. Thus it may form a 'false' receptor and trap dopamine molecules, thus diminishing the dopamine effect. Similarities between this proposed structure and a model of the molecular structure of the acetylcholine receptor are detailed.
Apomorphine↗
Use of nuclear magnetic resonance in determining molecular structure of urinary constituents of low molecular weight.
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Adenine↗
Molecular structures and magnetic resonance spectroscopic investigations of highly distorted six-coordinate low-spin iron(III) porphyrinate complexes.
Three bis-axially ligated complexes of iron(III) octaethyltetraphenylporphyrin, (OETPP)Fe(III), have been prepared, which are low-spin complexes, each with two axial nitrogen-donor ligands (N-methylimidazole (N-MeIm), 4-(dimethylamino)pyridine (4-NMe(2)Py), and 2-methylimidazole (2-MeImH)). The crystal and molecular structure of the bis-(2-MeImH) complex shows the macrocycle to be in a saddled conformation, with the ligands in perpendicular planes aligned at 14 degrees to the porphyrin nitrogens so as to relieve the steric interaction between the 2-methyl groups and the porphyrin. The Fe-N(por) bond lengths are typical of nonplanar six-coordinate low-spin Fe(III) complexes, while the axial Fe-N(ax) bond lengths are substantially longer than those of [(TPP)Fe(2-MeImH)(2)](+) (2.09(2) A as compared to 2.015(4) and 2.010(4) A). The crystal and molecular structure of the bis-(4-NMe(2)Py) complex also shows the macrocycle to be in a mainly saddled conformation, but with a significant ruffled component. As a result, the average Fe-N(por) bonds are significantly shorter (1.951 A as compared to 1.974 A) than those of the bis-(2-MeImH) complex. One ligand is aligned at 9 degrees to two trans porphyrin nitrogens, while the other is at 79 degrees to the same porphyrin nitrogens, producing a dihedral angle of 70 degrees between the ligand planes. The EPR spectrum of this complex, like that of the bis-(2-MeImH) complex, is of the "large g(max)" type, with g(max) = 3.29 and 3.26, respectively. However, in frozen CD(2)Cl(2), [(OETPP)Fe(N-MeIm)(2)](+) exhibits both "large g(max)" and normal rhombic signals, suggesting the presence of both "perpendicular" and "parallel" ligand orientations. The 1- and 2D (1)H NMR spectra of each of these complexes, as well as the chloroiron(III) starting material, were investigated as a function of temperature. The COSY and NOESY/EXSY spectra of the chloride complex are consistent with the expected J-coupling and saddle inversion dynamics, respectively. Complete spectral assignments for the bis-(N-MeIm) and -(4-NMe(2)Py) complexes have been made using 2D (1)H NMR techniques. In each case, the number of resonances due to methylene (two) and phenyl protons (one each) is consistent with D(2)(d)() symmetry, and therefore an effective perpendicular orientation of the axial ligands on the time scale of the NMR experiments. The temperature dependences of the (1)H resonances of these complexes show significant deviations from Curie behavior, and also evidence of extensive ligand exchange and rotation. Spectral assignment of the eight methylene resonances of the bis-(2-MeImH) complex to the four ethyl groups was possible through the use of 2D (1)H NMR techniques. The complex is fluxional, even at -90 degrees C, and ROESY data suggest that the predominant process is saddle inversion accompanied by simultaneous rotation of the axial ligands. Saddle inversion becomes slow on the 2D NMR time scale as the temperature is lowered in the ligand order of N-MeIm > 4-NMe(2)Py > 2-MeImH, probably due mainly to progressive destabilization of the ground state rather than progressive stabilization of the transition state of the increasingly "hindered" bis-ligand complexes.
Electron Spin Resonance Spectroscopy↗
Copper phthalocyanine labelled magnetic microcapsules: preparation, and binding properties in vitro and in vivo for mutagens having planar molecular structure.
Copper phthalocyanine tetrasulphonic acid (CPTS) functions were introduced into magnetic semi-permeable polyethyleneimine (PEI) microcapsules in order to create a recoverable scavenging system for trapping and biomonitoring, within the gastrointestinal cavity, of mutagens having a planar molecular structure. Stable ionic CPTS and covalent (thionylated CPTS, TCPTS) adducts to the microcapsule PEI were produced and shown to trap benzo[a]pyrene (B[a]P) in vitro in relation to the porphyrin/B[a]P ratio employed. 3-hydroxy B[a]P and B[a]P 3,6-dione from a crude B[a]P metabolite mixture, and a set of planar mutagens from crude opium/morphine pyrolysate mixtures could also be recovered in 7-86% yields after shaking with modified microcapsules followed by methanol/ammonia (50:1) desorption. Tetraols derived from B[a]P 7,8-diol-9,10 epoxide could also be recovered. Modified microcapsules were recovered magnetically from faeces of rats treated with [14C]B[a]P, and 45-51% of trapped radioactivity could be directly desorbed for HPLC assay compared with 30% for unmodified microscapsules. The relative extent of trapping by unmodified or CPTS- or TCPTS-modified microcapsules was different for various substrates, and it appears that the copper phthalocyanine tetrasulphonic acid moiety competes with another unidentified absorption/desorption structure in the microcapsules. These results show that selective and reversible trapping of carcinogens/mutagens having planar molecular structure can be achieved within the gastrointestinal tract.
Animals↗
Molecular structure design and synthetic approaches to the heterometallic alkoxide complexes (soft chemistry approach to inorganic materials by the eyes of a crystallographer).
General principles of formation and stability of the heterometallic alkoxides existing due to Lewis Acid-Base interaction, isomorphous substitution and heterometallic metal-metal bonds are discussed. The molecular structure design approach based on the choice of a proper molecular structure type and completing it with the ligands, providing both the necessary number of donor atoms and the sterical protection of the metaloxygen core, is presented. Its applications in prediction of the composition and structure of single source precursors of inorganic materials are demonstrated for such classes of compounds as oxoalkoxides, alkoxide beta-diketonates, alkoxide carboxylates, derivatives of functional alcohols, metallatranes and metallasiloxanes.
Journal Article↗