Quantum-chemical study of allylic and vinylic compounds of fifth-group elements

Energies and oscillator strengths of the long-wave electronic transitions for several conformers of allyl- and vinylamine and allyl- and vinylphosphine have been calculated by the semiempirical quantum-chemical MNDO method. The electronic structure of these molecules is discussed in detail, and the spectral and conformational effects ofn, and , conjugation are analyzed. Some suggestions concerning possible conjugation effects in the allylic compounds of As, Sb, and Bi are made.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1551–1554, September, 1993.     

Quantum-chemical study of the molecular and electronic structure of 2,2′-dithiodi(2-methyl-2,3-dihydro-1,4-thiazino[2,3,4-i,j]quinolinium)

Conformational isomerism of 2,2-dithiodi(2-methyl-2,3-dihydro-1,4-thiazino[2,3,4-i,j]quinolinium) has been studied by semiempirical MNDO and AM1 methods. Six symmetrical and unsymmetrical stationary states have been found. Optimum intramolecular rotations around single bonds have been considered. The possibility of the inversion of the reaction centers in nucleophilic and electrophilic reactions depending on the conformational state of the molecule has been shown. The spatial structure of one of the conformers found is similar to that typical of (–)-cystine. The observed constancy of some geometric and electronic parameters makes it possible to study the principal physicochemical properties of dithiazinoquinolinium compounds by the most sophisticatedab initio methods using small model structures, which are constructed by taking into account the variability of other geometric parameters, as an example.Deceased.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2359–2364, December, 1995.The work was supported by the Russian Foundation for Basic Research (Project No. 93-03-18400).     

Comparison of cyclic δ-opioid peptides with non-peptide δ-agonist spiroindanyloxymorphone (SIOM) using the message-address concept: A molecular modeling study

Summary Based upon the message-address concept, this molecular modeling study used the -selective agonist spiroindanyloxymorphone (SIOM) as a molecular template for a conformational search and analysis of -selective opioid peptides. It was assumed that the tyramine moiety plays the same role for -opioid receptor recognition in both peptide and non-peptide ligands. Using 20 reported low-energy conformations of Tyr-cyclo[d-Cys-d-Pen]-OH (JOM-13) for comparison, the geometrical relationship of the two aromatic rings present in SIOM was used for the identification of potential active conformations of JOM-13, from which two -receptor-binding models (I and II) were constructed. Models I and II differ from each other in the arrangement of the peptide backbones. To evaluate the two models, a conformational search of two other known -selective ligands, [d-Pen²,d-Pen⁵]enkephalin (DPDPE) and [d-Pen²,l-Pen⁵]enkephalin (DPLPE) was performed, using the geometrical relationship of the two aromatic rings defined in the two receptor-binding models as a molecular template. Among the conformations generated from the molecular simulation, low-energy conformers of DPDPE and DPLPE conforming to models I and II were identified. Unlike model I, conformers of DPDPE and DPLPE that fit model II contain a cis amide bond in the Gly³ residue.     

Molecular Lipophilicity Potential,a tool in 3D QSAR: Method and applications

Summary A new method is presented to calculate the Molecular Lipophilicity Potential (MLP). The method is validated by showing that the MLP thus generated on the solvent-accessible surface can be used to back-calculate log P. Because the MLP is shown to be sensitive to conformational effects, the MLP/log P relation is best sought by taking all conformers into account. The MLP method presented here can be used as a third field in CoMFA studies, as illustrated with two series of ₁ ligands. In the first series, the steric, electrostatic and lipophilic fields are highly intercorrelated, and taken separately yield comparable models. In the second series of ligands, the best model is obtained with the lipophilic field alone, allowing insights into ligand-receptor interactions.     

Highly conformationally constrained halogenated 6-spiroepoxypenicillins as probes for the bioactive side-chain conformation of benzylpenicillin

Summary The halogenated 6-spiroepoxypenicillins are a series of novel semisynthetic-lactam compounds with highly conformationally restricted side chains incorporating an epoxide. Their biological activity profiles depend crucially on the configuration at position C-3 of that epoxide. In derivatives with aromatic-containing side chains, e.g., anilide, the 3R-compounds possess notable Gram-positive antibacterial activity and potent-lactamase inhibitory properties. The comparable 3S-compounds are antibacterially inactive, but retain-lactamase inhibitory activity.Using the molecular simulation programs COSMIC and ASTRAL, we attempted to map a putative, lipophilic accessory binding site on the PBPs that must interact with the side-chain aromatic residue. Comparative computer-assisted modelling of the 3R, and 3S-anilides, along with benzylpenicillin, indicated that the available conformational space at room temperature for the side chains of the 3R and the 3S-anilides was mutually exclusive. The conformational space for the more flexible benzylpenicillin could accommodate the side chains ofboth the constrained penicillin derivatives. By a combination of van der Waals surface calculations and a pharmacophoric distance approach, closely coincident conformers of the 3R-anilide and benzylpenicillin were identified. These conformers must be related to the antibacterial, bioactive conformer for the classical-lactam antibiotics. From these proposed bioactive conformations, a model for the binding of benzylpenicillin to the PBPs relating the three-dimensional arrangement of a putative lipophilic S₂-subsite, specific for the side-chain aromatic moiety, and the 3-carboxylate functionality is presented.This work has been reported in preliminary form at the 4th Royal Society of Chemistry International Symposium on Recent Advances in the Chemistry of-lactam Antibiotics, Churchill College, Cambridge, U.K., 3–6 July 1988.     

The separation of the enantiomers of some potassium channel activators on α1-acid glycoprotein: the effect of solute conformationglycoprotein: the effect of solute conformation

Summary The amide conformers of two compounds and their enantiomers have been separated by liquid chromatography on an ₁-acid glycoprotein column. The effects of organic modifier and pH on the separations obtained were investigated. The conformers of one of the compounds were separated micro-preparatively at low temperature on the same column using a D₂O-based eluent; D₂O had no deleterious effects on the chromatography obtained. Some preliminary competition experiments on one of the amides and a close analogue are presented.     

Complementary molecular orbital investigations on the conformation of choline derivatives

Quantum-mechanical computations by the PCILO method, applied previously to the study of the conformational properties of acetylcholine and its derivatives modified in the central part of this molecule, are extended to modifications involving its cationic head and its ester terminal. The replacement of the methyl groups of the cationic head by hydrogens or ethyl groups leads to a steep decline in parasympathomimetic activity. It is shown that the triethyl derivative conserves the gauche form as the most stable one. The redistribution of the electronic charges at the onium group implies, however, a transition from an ionic to a hydrophobic binding. The replacement of the methyls by two or three hydrogens leads to a different preferred gauche-gauche conformation. The replacement of the methyl group at the ester terminal by a phenyl ring enables a comparison with the conformational properties of local anesthetics. The study brings about evidence, substantiated by NMR spectroscopy, that acetylcholine analogs and protonated local anesthetics are conformationally similar. Choline ethers also show a general preference for a gauche conformation. Nevertheless, biological studies do not indicate a constant correlation between conformation and biological potency. Conformational analogies or discrepancies alone cannot thus account for the fine details of the biological activity which must depend also on the electronic structure.This work was supported by the A.T.P. N A 655-2303 of the C.N.R.S.     

Excited states of phenyl carbonyl compounds

In an attempt to clarify the origin of the dual phosphorescence in phenyl alkyl ketones, we have made some calculation (within the C.I.P.S.I. method in an excitonic scheme) to elucidate the conformation of both ground states and excited states of propiophenone. Our calculations have shown the presence of two stable isomers in the ground state, first n ^* state, and first ^* singlet and triplet states. So our work suggests that the origin of the dual phosphorescence of propiophenone could be related to the conformational change of the molecule in the n ^* state, because the most stable conformations in the n ^* state and in the ground state are different.     

IR spectroscopic study of the conformational lability of 4′-ethyl-4-cyanobiphenyl

The conformational lability of 4-ethyl-4-cyanobiphenyl molecules in solid crystal (SC) and isotropic liquid (IL) states was investigated by IR spectroscopic techniques (experiment and theory). IR absorption spectra were measured at 28°C–95°C in the frequency range 400 cm^–1–4000 cm^–1. Spectrum simulation was performed using the fragment method with allowance for the conformational fluctuations of molecules. The experimental and calculated spectra were compared and analyzed, and it was shown that in the IL, the samples are mixtures of conformers. The temperature changes in the spectra in the stated range are caused by the conformational lability of molecules.Original Russian Text Copyright © 2004 by L. M. Babkov, I. I. Gnatyuk, G. A. Puchkovskaya, and S. V. TrukhachevTranslated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 3, pp. 398–405, May–June, 2004.     

Complex formation of hexakis(2,3,6-tri-O-methyl)-α-cyclodextrin with substituted benzenes in aqueous solution

The complex formation of hexakis (2,3,6-tri-O-methyl)--cyclodextrin with substituted benzenes has been investigated by circular dichroism (CD) spectroscopy. The sign and shape of the CD spectra markedly differ from the spectra of corresponding -cyclodextrin complexes because of the distorted conformation of the host molecule and/or the difference in the geometry of the host-guest interaction. Enthalpy and entropy changes of the complex formation are determined by using the CD band intensities measured at various temperatures and host concentrations. Negative values of H and S indicate that the hydrophobic interaction is not the major driving force for the complex formation. The guest molecule is suggested to be tightly bound within the host cavity through the induced-fit conformational change of the host molecule.     

Conformations of the thiathiophthenes and related molecules

A conformational ab initio MO study has been carried out for the thiathiophthene molecule (TTP) and two related model compounds, thiomalonaldehyde (TMA) and its conjugate base (TMA(-)). The conformational energy surfaces for TMA, TMA(-) and TTP were generated using a least squares fit to the calculated data and plotted on a CALCOMP plotter. The results of the calculations showed that the cis-cis planar conformation of TTP is the most stable in agreement with experimental findings. For TMA and TMA(-) the cis-cis planar conformation is not the most stable. Contour plots of the five occupied -MO's of TTP show great similarity to those of naphthalene.Less detailed calculations were carried out for 3-hydroxy-prop-2-en-1-thione (HPT) and 3-mercapto-prop-2-en-1-thione (MPT). HPT was shown to be most stable in the cis planar hydrogen bonded conformation in agreement with the experimentally obtained results. For MPT the non-hydrogen bonded planar structure was found to be the most stable.     

Quantum-chemical study of allylic compounds with two bonded heavy atoms

It has been shown by the CNDO method that the bathochromic shift of the long-wave absorption band in the transition from allylstannane to compounds of the type C=C-C-Sn-X and C=C-Sn-X (where X is a heavy atom) is connected with the formation of a low-energy vacant *_S-X orbital, localized mainly in the region of the Sn-X chemical bond, and of an occupied _Sn-X orbital, the energy of which is somewhat higher than of the _C-Sn orbital. The dependence of the position of the long-wave absorbance region on conformation is related to the fact that, in planar and nonplanar conformers, the long-wave transitions are of a different type ( * and *, respectively); the bathochromic shift is determined to a large degree by the difference in the energies of the highest occupied MO ( - ) in the s-trans form. In the nonplanar conformers the heavy atom orbitals interact with the -orbital of the ethylene moiety through the bridge group; this leads to a significant delocalization of the HOMO and to a considerable change in its energy. On the other hand, their interaction with the *-orbital in compounds of the C=C-C-Sn-X type is very low and does not favor the delocalization of lower vacant MO. In vinyldistannane the *-orbital is noticeably delocalized, due to the interaction with the *_Sn-Sn orbital in planar and with the *_Sn-Sn orbital in nonplanar conformers.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 3, pp. 636–641, March, 1992.     

The Heptakis-(2,6-di-O-methyl)-β-cyclodextrin Inclusion Complex with Acetic Acid

A novel monomer-type structure of heptakis-(2,6-di-O-methyl)--cyclodextrin in a typical monoclinic herringbone scheme has been determined by single crystal X-ray diffraction. Crystal data: space group P21, Z = 2, a = 15.165(6), b = 10.613(3), c = 23.188(8) Å, = 102.02(4)°, V = 3650(3) Å3 and R = 0.094 for 2933 observed MoK reflections with I > 3(I). A unique water molecule located in the intermolecular spaces, reinforces the cohesion between the herringbone chains. The analysis of the electron density distribution suggests that an acetic acid molecule is trapped within the macrocycle cavity, alternately with a water molecule.     

Binding of α-hydroxy-β-amino acid inhibitors to methionine aminopeptidase. The performance of two types of scoring functions

The binding mode of a recently described set of -hydroxy--amino acid inhibitors of methionine aminopeptidase type 2 is suggested in the present work. The binding mode is supported by analysis of published structures of transition state analogues co-crystallised with E. coli methionine aminopeptidase and by a comparison of molecular interaction fields calculated using GRID for E. coli and human methionine aminopeptidase. Based on the suggested binding mode two types of scoring functions have been evaluated and compared. These are the commercially available consensus score, CScore, and scoring of the ligands employing energies calculated using the Merck Molecular Force Field (MMFF). Enriched subsets of ligands were obtained when using CScore, but these scores could not be used to assess the relative affinities of individual compounds. Although still not sufficiently accurate for reliable predictive purposes, an improved correlation was obtained between structure and affinity using a combined force field energy including contributions from solvation and conformational energy penalty for binding.     

Theoretical Insights into the Formation, Structure, and Energetics of Some Cyclodextrin Complexes

To investigate the physicochemical aspects relevant for the formation of various cyclodextrin inclusion complexes and to search for corresponding general structure–complex-stability relationships, stability data of 1 : 1 complexes for 179, 310, and 51 guest molecules with unsubstituted -, -, and -cyclodextrin were collected. Statistical analysis using structure-based parameters such as molecular size, hydrophobicity, rotatable bonds, electronic properties, and the presence or absence of more than 150 various functional or structural moieties were performed. The complexation thermodynamics could be well described within the framework of our recently introduced molecular size-based model for nonassociative liquids. With increasing guest size, 1 : 1 complex stability, as measured by ln K or G⁰, increases linearly up to a size limit characteristic for each CD, and the corresponding slopes and intercepts are in agreement with those predicted by the model. For larger structures, values level off and are scattered around an average value depending on shape, goodness of fit, and possibly lipophilicity and some specific effects (e.g. such as those caused by presence of phenol functionality). The complexation between -cyclodextrin and certain large steroidal guest molecules, especially a brain-targeted estradiol chemical delivery systems (E₂-CDS) that is under clinical development, was investigated in details based on fully relaxed semiempirical AM1 quantum chemical calculations. A deformation index (DI) of the CD ring computed using these fully optimized host-guest geometries could be used to characterize the conformational change of the guest.     

Comparison of various hyphenated chromatography — Mass spectrometry methods for the analysis of β-agonists

Summary Different chromatography — mass spectrometry techniques for the analysis of -agonists have been compared.Gas chromatography — mass spectrometry (electron impact) has been used, as also has liquid chromatography coupled to the mass spectrometer by either thermospray or electrospray interfaces. The results obtained by the three method were compared in terms of sensitivity, selectivity, and richness of information provided by the analysis. It was found that using electrospray ionization, very powerful analysis could be achieved with high sensitivity, thus providing significant potential for the analysis of -agonists.     

Bilirubin conformational enantiomer selection in sodium deoxycholate chiral micelles

Intramolecularly hydrogen-bonded, bichromophoric tetrapyrrole pigments, bilirubin-IX and mesobilirubin-XIII, adopt either of two enantiomeric conformations which are in dynamic equilibrium in solution. InpH 8 aqueous sodium deoxycholate solutions, chiral micelles preferentially select one conformational enantiomer, and the solutions exhibit a bisignate circular dichroism Cotton effect in the vicinity of the bilirubin long wavelength electronic transition. Exciton coupling theory indicates a predominance of the left-handed (or negative) chirality bilirubin conformational enantiomer.     

Effect of hydrophobic amino acids on the conformational change of decapeptides in micellar environments

A series of peptides containing various hydrophobic amino acids [methionine (Met), leucine (Leu), norleucine (Nle), phenylalanine (Phe), 2-aminooctanoic acid (Aoc), and 2-aminodecanoic acid (Ade)] were synthesized and their conformations were studied using circular dichroism (CD) spectroscopy in different solvents such as water, methanol, and aqueous solution of ammonium tetradecanesulfonate. Peptides containing hydrophobic amino acids with linear side chains formed -sheets in water and methanol. Electrostatic interaction between the charged side chain (lysine) and a micelle consisting of an anionic surfactant, ammonium tetradecanesulfonate, is necessary for the formation of -helices in micellar environments. The conformational transition from -helix to -sheet structure required moderate hydrophobicity and linear side chains. This conformational transition depended on the surfactant concentration.     

Synthesis of Functionalized Spiro[cycloalkanono-2,3′-thiophenes] <Emphasis Type="Italic">via</Emphasis> Tandem Conjugate Addition-Cyclization of 3-Oxoacid Thioanilides to Nitroalkenes

Summary. A convenient method is described for the synthesis of functionalized spiro[cycloalkanono-2,3-thiophenes] by treatment of cyclic 3-oxoacid thioanilides with -nitrostyrenes. Reaction of the obtained products with acetic anhydride yielded the corresponding oxime acetates.     

A test of the Hirshfeld definition of atomic charges and moments

Summary The Hirshfeld population analysis scheme which carves the molecular density into atomic density contributions is tested. This method does not require a reference to basis sets or their respective locations, but is based on a different physical and mathematical footing. The advantage of this method is that, when the molecular deformation density converges to the true solution, the computed net charges will necessarily converge. This method also allows a straightforward definition for local moments. About 36 molecules have been used to compute the conventional Mulliken and Löwdin population analyses with STO3G, 6311G** and Dunning-Hay split valence basis sets. These results have been compared to the estimates provided by the Hirshfeld model. The charges found in the Hirshfeld method are smaller than those from the other methods.