Synthesis, spectral and conformational studies of some N-arylsulfonyl-t(3)-isopropyl-r(2),c(6)-diarylpiperidin-4-ones

A series of N-arylsulfonyl-t(3)-isopropyl-r(2),c(6)-diarylpiperidin-4-ones 1-8 were synthesized and characterized unambiguously by (1)H, (13)C NMR, 2D-COSY and HSQC NMR spectroscopy. The conformational preferences of 1-8 have been discussed on the basis of the coupling constants, and they suggest normal chair conformation with equatorial orientations of all the substituents in 1-8. The preferred conformation of aryl sulfonyl group at nitrogen and isopropyl group at C-3 was determined theoretically using density functional calculations.     

NMR studies of the conformational effect of single and double 3'-S-phosphorothiolate substitutions within deoxythymidine trinucleotides

NMR spectroscopy has been used to investigate the conformational effects of single and two consecutive 3'-S-phosphorothiolate modifications within a deoxythymidine trinucleotide. The presence of a single 3'-phosphorothioate modification shifts the conformation of the sugar ring it is attached to, from a mainly south to north pucker; this effect is also transmitted to the 3'-neighbour deoxyribose. This transmission is thought to be caused by favourable stacking of the heterocyclic bases. Similar observations have been made previously by this group. When two adjacent modifications are present, the conformations of the attached deoxyribose rings are again shifted almost completely to the north, however, there is no transmission to the 3' deoxyribose ring. Base proton chemical shift analysis and molecular modelling have been used to aid elucidation of the origin of this feature. The observation for the dimodified sequence is consistent with our previously reported results for a related system in which spaced modifications are more thermodynamically stable than consecutive ones.     

A theoretical study on three conformational structures of 2,6‐distyrylpyridine

Ab initio methods at the levels HF/cc‐pVDZ, HF/6‐31G(d,p), MP2/cc‐pVDZ, and MP2/6‐31G(d,p), as well as methods based on density functional theory (DFT) employing the hybrid functional B3LYP with the basis sets cc‐pVDZ and 6‐31G(d,p), have been applied to study the conformers of 2,6‐distyrylpyridine. Bond distances, bond angles, and dihedral angles have been calculated at the B3LYP level. The calculated values were in good agreement with those measured by X‐ray diffraction analysis of 2,6‐distyrylpyridine. The values calculated using the Hartree‐Fock method and second‐order perturbation theory (MP2) were inconsistent. The optimized lowest‐energy geometries were calculated from the reported X‐ray structural data by the B3LYP/cc‐pVDZ method. Three conformations, A, B, and C, were proposed for 2,6‐distyrylpyridine. Calculations at the three levels of theory indicated that conformation A was the most stable structure, with conformations C and B being higher in energy by 1.10 and 2.57 kcal/mol, respectively, using the same method and basis function. The same trend in the relative energies of the three possible conformations was observed at the two levels of theory and with the different basis sets employed. The reported X‐ray data were utilized to optimize total molecular energy of conformation A at the different calculation levels. The bond lengths, bond angles, and dihedral angles were then obtained from the optimized geometries by ab initio methods and by applying DFT using the two basis functions cc‐pVDZ and 6‐31G(d,p). The values were analyzed and compared. The calculated total energies, the relative energies of the molecular orbitals, the gap between them, and the dipole moment for each conformational structure proposed for 2,6‐distyrylpyridine are also reported. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

Modelling a 3D structure for EgDf1 from shape Echinococcus granulosus: putative epitopes, phosphorylation motifs and ligand

EgDf1 is a developmentally regulated protein from the parasite Echinococcus granulosus related to a family of hydrophobic ligand binding proteins. This protein could play a crucial role during the parasite life cycle development since this organism is unable to synthetize most of their own lipids de novo. Furthermore, it has been shown that two related protein from other parasitic platyhelminths (Fh15 from Fasciola hepatica and Sm14 from Schistosoma mansoni) are able to confer protective inmunity against experimental infection in animal models. A three-dimensional structure would help establishing structure/function relationships on a knowledge based manner.3D structures for EgDf1 protein were modelled by using myelin P2 (mP2) and intestine fatty acid binding protein (I-FABP) as templates. Molecular dynamics techniques were used to validate the models. Template mP2 yielded the best 3D structure for EgDf1. Palmitic and oleic acids were docked inside EgDf1.The present theoretical results suggest definite location in the secondary structure of the epitopic regions, consensus phosphorylation motifs and oleic acid as a good ligand candidate to EgDf1. This protein might well be involved in the process of supplying hydrophobic metabolites for membrane biosynthesis and for signaling pathways.     

Generate: a program for 3-D structure generation and conformational analysis of peptides and peptidomimetics

The program Generate, aimed at generating 3-D structures for peptides and peptidomimetics, is presented. The algorithm is based on a build-up procedure, using a library of conformations of amino acid residues. This library is built from conformational analysis of amino acids placed in a di- or tripeptide environment to mimic the surroundings of the amino acid in a true peptide, considering different positions of the residue in the peptide chain (peptidyl fragment, NH(+)(3)-terminus or COO(-)-terminus). Cis-trans isomerism in the amide bonds is taken into account by construction of rotamer libraries for different isomers. Water solvation is included through the GB/SA model. New amino acid residues can easily be added to the libraries, making it possible to generate conformations of peptidomimetics.     

The conformational stability of tactic poly(2-hydroxyethyl methacrylate) in aqueous salt solutions

The conformational stability of tactic poly(2-hydroxyethyl methacrylate) (PHEMA) in aqueous salt solutions was investigated by measurements of swelling, surface-free energy, and differential scanning calorimetry, as this polymer in water is sensitive in various electrolytes. In the case of inorganic salts, the major role for the salt effect is played by the anions, and the exposure of hydrophobic components at the PHEMA surface can be correlated with the increase of the degree of swelling. The influence of cations is considerably weaker. In the case of organic salts, tetraalkylammonium halides cause the chain extension more effectively with the increase of alkyl chain length in the cations. This result indicates that the breakdown of the hydrophobic parts in PHEMA provides an important clue on conformational stability. The amount of water molecules bound with the hydrophilic sites of tactic-PHEMA mainly depends on the chain extension and the hydration of cations. Since the sites in tactic-PHEMA influenced by the cation and the anion are different, their effects cause the conformational transition at a specific range of salt concentration. © 1993 John Wiley & Sons, Inc.     

A computational study of conformational interconversions in 1,4-dithiacyclohexane (1,4-dithiane)

Ab initio molecular orbital theory with the 6-31G(d), 6-31G(d,p), 6-31+G(d), 6-31+G(d,p), 6-31+G(2d,p), 6-311G(d), 6-311G(d,p), and 6-311+G(2d,p) basis sets and density functional theory (BLYP, B3LYP, B3P86, B3PW91) have been used to locate transition states involved in the conformational interconversions of 1,4-dithiacyclohexane (1,4-dithiane) and to calculate the geometry optimized structures, relative energies, enthalpies, entropies, and free energies of the chair and twist conformers. In the chair and 1,4-twist conformers the C-Hax and C-Heq bond lengths are equal at each carbon, which suggest an absence of stereoelectronic hyperconjugative interactions involving carbon-hydrogen bonds. The 1,4-boat transition state structure was 9.53 to 10.5 kcal/mol higher in energy than the chair conformer and 4.75 to 5.82 kcal/mol higher in energy than the 1,4-twist conformer. Intrinsic reaction coordinate (IRC) calculations showed that the 1,4-boat transition state structure was the energy maximum in the interconversion of the enantiomers of the 1,4-twist conformer. The energy difference between the chair conformer and the 1,4-twist conformer was 4.85 kcal/mol and the chair-1,4-twist free energy difference (deltaG degrees (c-t)) was 4.93 kcal/mol at 298.15 K. Intrinsic reaction coordinate (IRC) calculations connected the transition state between the chair conformer and the 1,4-twist conformer. This transition state is 11.7 kcal/mol higher in energy than the chair conformer. The effects of basis sets on the 1,4-dithiane calculations and the relative energies of saturated and unsaturated six-membered dithianes and dioxanes are also discussed.     

Molecular modeling of polymers. 10. Characterization of conformational transitions of poly(acrylic acid) and poly(methacrylic acid) using dyad structures

The conformational profiles of nearest side-chain neighbors, methylene-dyad structures, of poly(acrylic acid), PAA, and poly(methacrylic acid), PMA, were determined as a function of tacticity, extent of ionization, and presence of counterion. The dominant backbone conformer states are quite similar for both isotactic and syndiotactic diads in a common charge state. Thus, the overall dimensional properties of isotactic syndiotactic and atactic chains of PAA or PMA, based upon dyad interactions, are predicted to be alike for a given charge state. Significant deviations from precise t, g⁺, and g^? states are found for the dyad minimum energy conformations. The rod-to-coil and coil-to-rod transitions observed in PAA and PMA, respectively, as a function of increasing counterion concentration can be explained, to a large extent, by the conformational profiles of the corresponding dyad model structures. © 1994 John Wiley & Sons, Inc.     

A CoMFA analysis with conformational propensity: An attempt to analyze the SAR of a set of molecules with different conformational flexibility using a 3D-QSAR method

CoMFA analysis, a widely used 3D-QSAR method, has limitations to handle a set of SAR data containing diverse conformational flexibility since it does not explicitly include the conformational entropic effects into the analysis. Here, we present an attempt to incorporate the conformational entropy effects of a molecule into a 3D-QSAR analysis. Our attempt is based on the assumption that the conformational entropic loss of a ligand upon making a ligand-receptor complex is small if the ligand in an unbound state has a conformational propensity to adopt an active conformation in a complex state. For a QSAR analysis, this assumption was interpreted as follows: a potent ligand should have a higher conformational propensity to adopt an `active-conformation'-like structure in an unbound state than an inactive one. The conformational propensity value was defined as the populational ratio, N<sub>active</sub>/N<sub>stable</sub>, of the number of energetically stable conformers, N<sub>stable</sub>, to the number of `active-conformation'-like structures, N_active. The latter number was calculated by counting the number of conformers that satisfied the structural parameters deduced from the active conformation. A set of SAR data of imidazoleglycerol phosphate dehydratase inhibitors containing 20 molecules with different conformational flexibility was used as a training set for developing a 3D structure-activity relationship by a CoMFA analysis with the conformational propensity value. This resulted in a cross-validated squared correlation coefficient of the CoMFA model with the conformational propensity value (R ² _cross = 0.640) higher than that of the standard CoMFA model (R ² _cross = 0.431). Then we evaluated the quality of the CoMFA models by predicting the inhibitory activity for a new molecule.     

Solvent and temperature effects on the conformational equilibria of a dihydrobenzo[h]quinolinium fluoroborate

Spectra of the N‐phenyl‐5,6‐dihydro‐2,4‐diphenylbenzo[h]quinolinium tetrafluoroborate (1) and of the N‐phenyl‐5,6,8,9‐tetrahydro‐7‐phenyldibenzo[c,h]acridinium tetrafluoroborate (2) were recorded in various solvents and temperatures. The analysis of the ¹H‐NMR spectra of the tetrafluoroborate salt 1, recorded in acetone, acetonitrile, 1,1,2,2‐tetrachloroethane and chloroform, revealed the existence of an equilibrium between two conformers in solution. Tight ion‐pairing in chloroform led to a smaller barrier for interconversion between the two conformers. In more polar solvents, where the dihydrobenzoquinolinium exists as a free cation, theoretical calculations predicted larger barriers. The spectra of 1 in 1,1,2,2‐tetrachloroethane also varied with temperature, resembling at higher temperatures the spectrum in CDCl₃ and at 300K spectra in more polar media. Spectra of 2 did not vary with the solvent or the temperature, in an indication of a much higher barrier to conformational interconversion, because of a greater steric hindrance between the N‐phenyl substituent and the dihydrobenzo rings. Copyright © 2009 John Wiley & Sons, Ltd.     

Identification of a Glypican‐3‐Binding Peptide for In Vivo Non‐Invasive Human Hepatocellular Carcinoma Detection

Early and accurate detection of hepatocellular carcinoma (HCC) is essential to improve the prognosis of patients and reduce the morbidity of surgical therapy. Glypican‐3 (GPC3) is a protein abnormally expressed in HCC that has been identified as a serological and histochemical HCC marker. A novel peptide that specifically recognizes GPC3 will facilitate early detection of HCC and guide the treatment strategy. Herein, phage display screening technology is utilized to obtain a GPC3 binding peptide (GBP) using HCC cells expressing GPC3 in varying abundances. After seven rounds of panning, a peptide with sequence of THVSPNQGGLPS is identified with 735.2 ± 53.6 × 10⁻⁹ m affinity to GPC3. The ability to target GPC3 in vivo is evaluated by intravenous injection of GBP labeled with a near‐infrared dye, Cy5.5, into a HCC tumor‐bearing mouse model. Significant high tumor accumulation (tumor/muscle ratio: 6.49 ± 0.55) of Cy5.5‐GBP in HepG2 tumors is observed compared with that of the low GPC3 expressing prostate cancer cell line, PC3 (tumor/muscle ratio: 1.15 ± 0.32). By targeting GPC3, GBP differentiates tumor tissues from normal liver tissues in patients, suggesting a great clinical translation potency of GBP. Collectively, GBP demonstrates great potential for HCC detection via fluorescent imaging or histological staining.

     

Chemical shift assignment and conformational analysis of monoalkylated acylguanidines

Monoalkylated acylguanidines are important functional groups in many biologically active compounds and additionally applied in coordination chemistry. Yet a straightforward assignment of the individual NH chemical shifts and the acylguanidine conformations is still missing. Therefore, in this study, NMR spectroscopic approaches for the chemical and especially the conformational assignment of protonated monoalkylated acylguanidines are presented. While NOESY and ³J_{H, H} scalar couplings cannot be applied successfully for the assignment of acylguanidines, ⁴J_{H, H} scalar couplings in ¹H,¹H COSY spectra allow for an unambiguous chemical shift and conformational assignment. It is shown that these ⁴J_{H, H} long‐range couplings between individual acylguanidinium NH resonances are observed solely across all‐trans (w) pathways. Already one cis orientation in the magnetisation transfer pathway leads to signal intensities below the actual detection limit and significantly lower than cross‐peaks from ²J_{NH, NH} couplings or chemical exchange. However, it should be noted that also in the case of conformational exchange being fast on the NMR time scale, averaged cross‐peaks from all‐trans ⁴J_{H, H} scalar couplings are detected, which may lead at first glance to an incomplete or even wrong conformational analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

Computational studies on the conformational preference of N-(Thiazol-2-yl) benzamide

N-(Thiazol-2-yl) benzamide 1 substructures are found in some of bioactive compounds. In some of protein/ligand co-crystals, the 1 moiety adopts a conformer in which the amide O and the thiazole S atoms are close. In fact, in the crystalline structure of 1 , the O—S distance is even shorter than Van der Waals radius. Although the natural bond orbital analysis finds a weak stabilizing interaction between O and S atoms, the attractive dipole–dipole interaction between the amide N─H and thiazole N atom seems to play a more significant role. Moreover, an intramolecular O—H hydrogen bonding in dimeric forms found to have an important role in the conformation preference of 1 . Computational details for the stability of conformers have been discussed using quantum theory of atoms in molecules, natural bond orbital (NBO) and noncovalent interaction index analysis.     

Synthesis of novel VO (II)‐thaizole complexes; spectral,conformational characterization,MOE‐docking and genotoxicity

New VO (II)‐thaizolyl hydrazine complexes were synthesized and characterized by analytical, spectral and theoretical techniques. Bi‐nuclear complexes were suggested for all synthesizes upon neutral poly‐dentate mode of bonding. UV–Vis and EPR spectra, proposed two structural geometries as, square‐planer and octahedral. TGA confirmed the contribution of solvent molecules through physical and/or coordinate‐bonding. XRD parameters calculated, displayed outstanding nanometer‐sizes for all nano‐crystalline compounds, which suffering slight imperfections. Also, SEM images showed, spherical‐shape that observed for most topographic particulates. Conformational study executed for all new synthesizes, demonstrated their optimized structural‐forms. Furthermore, important physical parameters were computed that predict essential characteristics as, biological efficiency. Predictable parameters as softness and electrophilicity, point to priority of VO (II)‐4d complex. Genotoxic study, was already examined, for all new synthesizes, against CT‐DNA and displayed complete deterioration for DNA, by influence of most tested compounds. Moreover, MOE‐docking technique, was executed against receptors of Y‐family DNA‐polymerase (4irk) and Key‐Enzyme Linking‐Metabolic Inflammation (4cyf). This docking study displayed the following ascending order; VO (II)‐4c,4irk ? VO (II)‐4d,4cyf ? VO (II)‐4c, 4cyf ? VO (II)‐4b, 4cyf, based on scoring‐energy values. This study concluded with promising prediction of these complexes in relation to DNA‐polymerase as well as inflammation enzyme that compared with known anti‐inflammatory drug (meloxicam).     

Analysis of B3LYP and MP2 conformational population distributions in trans‐nicotine,acetylcholine, and ABT‐594

This work presents an analysis of the equivalence of MP2 and DFT (B3LYP functional) conformational populations. As a test case, we select three cholinergic agents (trans‐nicotine, acetylcholine, and the nicotinic analgesic ABT‐594), where the minima on the conformational energy hypersurfaces expand a large range of energies (～0–30 kJ mol^?1). From energetic and structural data obtained in vacuo at the MP2 and B3LYP/cc‐pVDZ levels, we build conformational partition functions, including the effect of the conformational kinetic energy and the rotovibrational coupling. Our results at a physiological temperature (37°C) show qualitative agreement in all cases. Quantitative agreement, however, is only found for trans‐nicotine and ABT‐594. In the first case, energy minima differ by <0.2 kJ mol^?1. Therefore, the equivalence of structural results translates in the equivalence of the conformational distribution. For ABT‐594, the minima are separated by as much as 8.0 kJ mol^?1, and the conformational energy determines the conformational distribution. In this case, the slight relative variation of conformational energy, between B3LYP and MP2, does not affect the population, since the secondary minima are high in energy and very low in population. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Temperature‐dependent conformational analysis of cyclononane: An ab initio study

Quantum chemical methods were used for the theoretical determination of the conformational population for the relevant conformers of cyclononane, i.e., TBC, TCB, TCC, and M4 (or C1), which have been previously investigated experimentally through detailed examination of the nuclear magnetic resonance (NMR) spectrum. Our best Gibbs free energy result, evaluated with MP4(SDTQ)/6‐31G(d,p)//MP2/6‐31G(d,p) energy differences and MP2/6‐31G(d,p) thermal corrections, lead to a temperature‐dependent population in excellent agreement with the experimental results based on the analysis of the low temperature ¹³C NMR spectrum. The nice agreement with experiment is achieved using MP2 harmonic frequencies for the evaluation of vibration partition functions within the standard statistic thermodynamics formalism. Theoretical temperature‐dependent infrared (IR) and ¹³C NMR spectra were simulated and compared with experimental data, which confirmed the ab initio conformational population reported here. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007