NMR and X-ray crystallographic studies of the conformation of a 3,4,6-triphenyl-delta-lactone.

1-Oxa-3S,4S,6R-triphenyl-2-cyclohexanone and its enantiomer were synthesized, and the structure was determined by NMR and X-ray crystallography. The X-ray crystal structure showed that the delta-lactone adopts a boat conformation in the solid. The X-ray data showed a shortened C-O bond between the carbonyl carbon and the ether oxygen, consistent with delocalization involving the ester group. (1)H and (13)C NMR measurements in acetone-d(6) showed that the lactone is biased in favor of a boat conformation. In the less polar solvent chloroform-d(1), changes in the (1)H NMR coupling constants indicate a shift in the equilibrium in favor of a less rigid twist-boat conformation. The IR absorption of the lactone carbonyl at 1740 cm(-)(1) would suggest a half-chair conformation inconsistent with the dominance of the boat forms shown by NMR and X-ray.     

Conformational analysis of mixed oxathia crown ethers and their complexational ability towards Ag(I) and Pd(II)-an experimental solution NMR and theoretical molecular modelling study

Both the conformation and flexibility of four mixed oxathia crown ethers and their Ag(I) and Pd(II) complexes were studied by (1)H NMR (delta, J, NOE, T(1)), (13)C NMR, dynamic (1)H NMR spectroscopy and molecular modelling. The stoichiometry and stability constants of the complexes were determined from corresponding Job's plots in the case of Ag(I) complexes as the interchange between free and complexed states was fast on the NMR timescale; interchange for the Pd(II) complexes was sufficiently slow such that distinct sub-spectra were observable for the free and complexed states. In all cases where complexation was observed, 1 : 1 complexes were formed. Global minima structures determined from the modelling studies were analysed with respect to the barriers to ring interconversion, the flexibility of the species in solution and the preferred complexation of Ag(I) and Pd(II) to the sulfur atoms of the crown ethers.     

A novel mechanism of antibiotic resistance: study of the complex state of peptides with bacterial Staphylococcus aureus ribosomes

Two antibiotic resistance peptides, the E-peptide (MRLFV) and the K-peptide (MRFFV) conferring macrolide and ketolide resistance, respectively, were studied in the complex state with bacterial Staphylococcus aureus ribosomes after a conformational analysis by NMR spectroscopy and molecular modeling of the unbound molecules. T2 (CPMG) measurements were used to characterize equilibrium binding of antibiotic resistance peptides to bacterial ribosomes. Additionally, interactions of antibiotic resistance peptide to ribosomes were investigated using two-dimensional transferred nuclear Overhauser effect spectroscopy (TRNOESY), resulting in bound structures compatible with the experimental NMR data.     

Determination of the preferred conformation of the bicyclic Galerucella pheromone using density functional theory optimization and calculations of chemical shifts

A pheromone from the beetle, Galerucella calmariensis, was recently isolated and identified (Bartelt, R. J. et al. J. Chem. Ecol. 2006, 32, 693-712) as a 14-carbon, bicyclic dimethylfuran lactone, with the systematic name 12,13-dimethyl-5,14-dioxabicyclo[9.2.1]tetradeca-1(13),11-dien-4-one. The main 12-membered lactone ring is very flexible; as a result, there exist multiple possible conformations. The preferred conformation cannot be deduced solely from room-temperature NMR measurements. Using density functional (DFT) studies, 26 unique conformers with energies within 10.0 kcal/mol of the global minimum-energy structure were found. A mirror-image plane exists so that each conformer has an "inverse" structure with the same energy, for which the dihedral angles around the flexible ring have opposite sign. The isotropic 1H and 13C NMR chemical shifts of the DFT-optimized structures were calculated using the gauge-including atomic orbital (GIAO) method. By considering the relative energies of the conformers and the calculated and observed NMR spectra, we concluded that the molecule exists primarily as a mixture of two distinct conformers at room temperature, each being present with its mirror-image inverse. Structural interconversions among these likely occur on a time scale that is fast compared to the NMR experiments. Using mode-following and dihedral-driving techniques, several potential pathways were found for the conversion of the lowest-energy conformer to its mirror-image structure. Ab initio molecular dynamics (AIMD) using the 4-31G basis set was carried out for 50 ps to test the availability of various low-energy minima and the transition states found from the searches noted above.     

Molecular mechanics conformational analysis of tylosin

The conformations of the 16-membered macrolide antibiotic tylosin were studied with molecular mechanics (AMBER* force field) including modelling of the effect of the solvent on the conformational preferences (GB/SA). A Monte Carlo conformational search procedure was used for finding the most probable low-energy conformations. The present study provides complementary data to recently reported analysis of the conformations of tylosin based on NMR techniques. A search for the low-energy conformations of protynolide, a 16-membered lactone containing the same aglycone as tylosin, was also carried out, and the results were compared with the observed conformation in the crystal as well as with the most probable conformations of the macrocyclic ring of tylosin. The dependence of the results on force field was also studied by utilizing the MM3 force field. Some particular conformations were computed with the semiempirical molecular orbital methods AM1 and PM3.     

Conformational study of (8alpha,8'beta)-bis(substituted phenyl)-lignano-9,9'-lactones by means of combined computational, database mining, NMR, and chemometric approaches

Beta-(3,4-Methylenedioxybenzyl)-gamma-butyrolactone (MDBL) and (-)-hinokinin (HK) were obtained by partial synthesis and characterized by 1H NMR and computational methods (conformational analysis, molecular modeling, structural data mining and chemometrics). Three conformers were detected for MDBL and nine were found for HK. The energy differences are around 1 and 2 kcal mol(-1) and rotation barriers are less than 3 and 5 kcal mol(-1) for MDBL and HK conformers, respectively. The geometries of these conformers, obtained from semiempirical PM3 and density functional theory (DFT) B3LYP 6-31G** calculations agree satisfactorily with 1H NMR data (vicinal proton-proton coupling constants) and structures retrieved from the Cambridge Structural Database (torsion angles). DFT combined with some variants of the Haasnoot-de Leeuuw-Altona equations gives the best predictions for the coupling constants. The molecular conformation of MDBL, of HK, and of related systems depends not only on intramolecular interactions but also on crystal packing forces and solvent-solute interactions, in particular hydrogen bonds and polar interactions. Hydration favors more stable HK conformers, which can be important for their behavior in chemical and biological systems.     

Comparison of 17beta-estradiol structures from x-ray diffraction and solution NMR

The NMR-derived structure of estrogen (17beta-estradiol, E2), the drug of choice for postmenopausal women, was compared with a recent literature crystal x-ray structure of Fab-bound E2. 1H and 13C NMR spectra of E2 were acquired in DMSO-d6. Assignments were obtained from an analysis of DQF-COSY, TOCSY, HETCOR, HMQC and HMBC 2D NMR spectra. The 1H and 13C NMR assignments are the first reported for E2 in DMSO-d6. Two solution structures, S1 and S2, were obtained with molecular modeling using NOE constraints. S1 overlaps with the crystal structure for all rings. S2 shows prominent differences in the C-ring (C9--C11--C12--C13) segment, which deviates from a chair conformation, and excellent overlap in the A-, B- and D-rings of E2. The C-ring in S2 adopts a boat conformation as opposed to a chair conformation in the x-ray and S1 structures. The S2 structure is about 6 degrees more twisted than the bound x-ray and S1 models. The S1, S2 and x-ray structures had ring bowing values of 10.1 +/- 0.3, 11 +/- 1 and 10.37 degrees , respectively. Of the 100 solution conformers generated, 83 had S1 conformation and 17 had S2 conformation, with average internal energies of 112 +/- 2 and 141 +/- 2 kcal mol(-1), respectively. The 100 S1- and S2- derived conformers showed a r.m.s.d. of 0.72 A for all atoms. The x-ray, S1 and S2 C18--O17 distances were 2.93, 2.92 +/- 0.01 and 2.93 +/- 0.01 A, respectively, and the O3--O17 distances were 11.06, 11.18 +/- 0.12, and 10.89 +/- 0.05 A, respectively.     

Conformational and docking studies of acyl homoserine lactones as a robust method to investigate bioactive conformations

A method aiming at investigating possible bioactive conformations of acyl homoserine lactone (AHL) quorum sensing (QS) modulators is established. The method relies on the exhaustive conformational analysis of AHLs by varying torsion angles around the amide group then on the selection of the closest conformation to those known from co-crystallized XRD data of AHL-receptor complexes. These latter are then docked as rigid ligand within the receptor binding site, leading to interactions with binding site residues which are highly consistent as compared with the data arising from XRD studies. The method is first validated using AHLs for which XRD data of their complexes with their cognate receptor are available, then extended to examples for which the binding mode is still unknown.Three compounds were used to validate the method: hexanoyl homoserine lactone (HHL) as an example of autoinducer, 3-oxo-butanoyl homoserine lactone (OBHL), as a representative model of 3-oxo-AHLs, and 4-(4-chlorophenoxy)butanoyl homoserine lactone (CPOBHL) as an example of a QS inhibitor. The conformational analysis of these three compounds to their cognate protein (TraR, SdiA, LasR and CviR) provides the data which enable the next rigid docking step. Further rigid docking of the closest conformations compared to the known bioactive ones within the binding sites allows to recover the expected binding mode with high precision (atomic RMSD < 2 Å). This “conformational analysis/torsion angle filter/rigid ligand docking” method was then used for investigating three non-natural AHL-type QS inhibitors without known co-crystallized XRD structures, namely was 2-hexenoyl homoserine lactone (HenHL), 3-oxo-4-phenylbutanoyl homoserine lactone (OPBHL) and 3-(4-bromophenyl)propanoyl homoserine lactone (BPPHL). Results provide insights into their possible binding mode by identifying specific interactions with some key residues within the receptor binding site, allowing discussion of their biological activity.     

溶液中N—乙酸基取代氮氧杂大环的构象及其配合物的NMR研究

用~1HNMR方法研究了溶液中大环化合物1,12-二氮杂-3,4:9,10-二本并-5,8-二氧杂环十五烷-N,N’-二乙酸盐的构象.NMR变温实验表明,在溶液中大环与Zn(Ⅱ)、Ni(Ⅱ)、Co(Ⅱ)的配合物环上醚氧不参与配位,其中Ni(Ⅱ)配合物为低自旋反磁性的平面四方形配位.     

Chiral recognition by CD-sensitive dimeric zinc porphyrin host. 2. Structural studies of host-guest complexes with chiral alcohol and monoamine conjugates.

A structural study of complexes formed between a dimeric zinc porphyrin tweezer (host) and chiral monoalcohols and monoamines derivatized by a bidentate carrier molecule (guest) confirmed that their CD couplets arise from the preferred porphyrin helicity of 1:1 host-guest complexes. NMR experiments and molecular modeling of selected tweezer complexes revealed that the preferred conformation is the one in which the L (larger) group protrudes from the porphyrin sandwich; this preferred helicity of the complex determines the CD of the complexes. It was found that the porphyrin ring-current induced (1)H chemical shifts and molecular modeling studies of the complex lead to the assignments of relative steric size of the L (large)/M (medium) substituents attached to the stereogenic center. The assignments, in turn, are correlated with the sign of the CD exciton couplet that establishes the absolute configuration at the stereogenic center. Variable-temperature NMR experiments proved that the observed increase in CD amplitude at lower temperatures derives from conformational changes in the preferred offset geometry between two porphyrin rings.     

The structural characterization of some palladium (Ⅱ) complexes of 1,10-phenanthroline and amino acids by NMR spectroscopy

The complexes [Pd(phen)(aa)]Cl.3H2O, where phen is 1,10-phenanthroline and aa is the anion of glycine (gly), .DL-alanine (ala), DL-serine (ser) or DL-asparagine (asn), were synthesized and characterized by spectroscopies. The NMR signals were assigned completely on the basis of the double irradiation, 1H-1H COSY and 1H-13C COSY techniques. In the 1H NMR spectra of phen in the complexes, the signals of 2-H and 9-H show upfield shifts 0.8-1 ppm, while the signals of 4-H and 3-H show downfield shifts or almost no shift, as compared to the free phen ligand, and the signal of 4-H appears in the lowest field. The signals of ring B which is trans to the carboxyl group show significant upfield shifts as compared to those of ring A. The probable structures were described on the basis of a metal-non-bonded hydrogen interaction, trons effect and ligand-ligand interaction. There may exist three conformation isomers in the [Pd(phen)(asn)]Cl.3H2O complex at room temperature. The preferred conformation isomer is about     

Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions

DNA methyltransferases (DNMTs) including DNMT1 are a conserved family of cytosine methylases that play crucial roles in epigenetic regulation. The versatile functions of DNMT1 rely on allosteric networks between its different interacting partners, emerging as novel therapeutic targets. In this work, based on the modeling structures of DNMT1-ubiquitylated H3 (H3Ub)/ubiquitin specific peptidase 7 (USP7) complexes, we have used a combination of elastic network models, molecular dynamics simulations, structural residue perturbation, network modeling, and pocket pathway analysis to examine their molecular mechanisms of allosteric regulation. The comparative intrinsic and conformational dynamics analysis of three DNMT1 systems has highlighted the pivotal role of the RFTS domain as the dynamics hub in both intra- and inter-molecular interactions. The site perturbation and network modeling approaches have revealed the different and more complex allosteric interaction landscape in both DNMT1 complexes, involving the events caused by mutational hotspots and post-translation modification sites through protein-protein interactions (PPIs). Furthermore, communication pathway analysis and pocket detection have provided new mechanistic insights into molecular mechanisms underlying quaternary structures of DNMT1 complexes, suggesting potential targeting pockets for PPI-based allosteric drug design.     

CoMFA 3D-QSAR analysis of HIV-1 RT nonnucleoside inhibitors, TIBO derivatives based on docking conformation and alignment

HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as nonnucleoside RT inhibitors (NNRTIs) and nucleoside analogues. NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTI category, there is a set of inhibitors commonly referred to as TIBO inhibitors. Fifty TIBO inhibitors were used in the work to build 3-D QSAR models. The two known crystal structures of complexes are used to investigate and validate the docking protocol. The results show that the docking simulations reproduce the crystal complexes very well with RMSDs of approximately 1 A and approximately 0.6 A for 1REV and 1COU, respectively. The alignment of molecules and "active" conformation selection are the key to a successful 3D-QSAR model by CoMFA. The flexible docking (Autodock3) was used on determination of "active" conformation and molecular alignment, and CoMFA and CoMSIA were used to develop 3D-QSAR models of 50 TIBOs in the work. The 3D-QSAR models demonstrate a good ability to predict the activity of studied compounds (r2 = 0.972, 0.944, q2 = 0.704, 0.776). It is shown that the steric and electrostatic properties predicted by CoMFA contours can be related to the binding structure of the complex. The results demonstrate that the combination of ligand-based and receptor-based modeling is a powerful approach to build 3D-QSAR models.     

Preparation of Poly(serine ester)s by Ring-opening Polymerization of N-Trityl Serine Lactone Under Catalysis of ZnEt2

Poly(N-trityl serine lactone)(PTSL) and mPEG-block-poly(N-trityl serine lactone)(mPEG-b-PTSL, PEG=polyethylene glycol) were synthesized via the ring-opening polymerization of N-trityl serine lactone(TSL) with diethyl zinc(ZnEt₂) as catalyst. The structures of these polymers were confirmed with hydrogen nuclear magnetic resonance(¹H NMR) spectroscopy, carbon nuclear magnetic resonance(¹³C NMR) spectroscopy and infrared(IR) spectrometer. The thermal decomposition temperature and glass transition temperature of PTSL were 241 and 161 ℃, respectively. A series of mPEG-b-PTSL with different molecular weights(M_n's from 7000 to 32000) was obtained by tuning the TSL/mPEG feed ratio. After the removal of the trityl groups, mPEG-block-poly(serine lactone)(mPEG- b-PSL) was obtained as a new kind of cationic block copolymer. Low cytotoxicity of these polymers to L929 cells was confirmed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay.     

meso-四(对烷氧基苯基)卟啉镁配合物的合成、表征和性能研究

合成了一系列meso-四(对烷氧基苯基)卟啉镁配合物,用UV-Vis,1H NMR,IR,MS,元素分析等确证了配合物的结构,总结了镁与卟啉类配体配合的UV-Vis,1H NMR,IR数据.采用差示扫描量热法(DSC)和偏光显微镜(PM)研究了该系列配合物的液晶性能,发现6个配合物具有液晶性;考察了烷氧基链长、配位金属离子和分子空间结构对液晶性能的影响.     

Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling

Conformations of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative were determined in various solvents. The experimental NMR data--coupling constants and NOE contacts--were compared with the results of molecular modelling--molecular mechanics calculations and molecular dynamics simulations. The conformational changes, on the right-hand side of the 14-membered ring, affected mostly the 3JH2,H3 values and NOE crosspeaks H3 or H4 to H11. Oleandomycin was found to be present predominantly in the C3-C5 folded-in conformations in DMSO-d6 solution, whereas in buffered D2O, acetone-d6 and CDCl3, there was a mixture of folded-in and folded-out conformational families. The predominant conformation of the 8-methylene-oleandomycin-9-oxime derivative in solution was a folded-out one although different amounts of folded-in conformation were also present depending on the solvent. Oleandrose and desosamine sugar moieties adopted the usual and expected chair conformation. The conformation around the glycosidic bonds, governing the relative orientation of sugars vs. the lactone ring, showed a certain flexibility within two conformationally close families. We believe that by combining the experimental NMR data and the molecular modelling techniques, as reported in this paper, we have made significant progress in understanding the conformational behaviour and properties of macrolides. Our belief is based on our own current studies on oleandomycins as well as on the previously reported results and best practices concerning other macrolides. A rational for macrolide conformational studies and advances in methodology has been suggested accordingly.     

Vinyl polymerization of norbornene catalyzed by 2‐Py‐amidine Ni(II) complex/methylaluminoxane systems

Two 2‐Py‐amidine ligands (2‐Py―NH―C(Ph)═N―Ar, Ar = 2,6‐Me₂C₆H₃ and 2,6‐ⁱPr₂C₆H₃) and the corresponding Ni(II) complexes ( 1 and 2 ) were synthesized and characterized using elemental analysis and FT‐IR, UV–visible, ¹H NMR and ¹³C NMR spectroscopies. X‐ray crystal structures indicate that the chelate ring conformation of the less bulky complex 1 is relatively planar compared with that of the bulky complex 2 . Paramagnetic ¹H NMR and ¹³C NMR studies show that, in solution, the time‐average structures of complexes 1 and 2 have mirror symmetry. Both complexes 1 and 2 were used as catalyst precursors for norbornene polymerization with methylaluminoxane as a co‐catalyst. The effects of Al/Ni ratio, temperature and structure of precursors on the catalytic performance were investigated. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis and spectrothermal studies on group 12 metals coordination with novel carboxyamide ligands

Complexes of group 12 metals with new ligands N',N'-bis(3-carboxy-1-oxopropanyl) 2-amino-N-arylbenzamidine (H2L) and N',N'-bis(3-carboxy-1-oxophenelenyl) 2-amino-N-arylbenzamidine (H(2)L) have been synthesized and characterized by elemental analyses, vibrational spectra, electronic spectra, (1)H NMR spectra, TOF-mass spectra, thermal studies and molecular modeling studies. The infrared and (1)H NMR spectral data are in agreement with coordination of amide and carboxylate oxygen of the ligands giving a MO(4) tetrahedral chromophore. The elemental analyses and mass spectral data have justified the ML complexes. The thermal behaviour of complexes shows that water molecule is removed in first step--followed by decomposition of the rest of the molecule in the next steps. Kinetic and thermodynamic parameters were computed from the thermal data using Coats and Redfern method, which confirm first order kinetics. Molecular structures of the complexes have been optimized by MM2 calculations and supported tetrahedral geometry around metal(II) ions.     

Synthesis and conformational analysis of small peptides containing 6-endo-BT(t)L scaffolds as reverse turn mimetics

Two new dipeptide isosteres derived from L-leucine and meso-tartaric acid derivatives, named 6-endo-BTL and 6-endo-BtL, were inserted in a small peptide by means of SPPS, and the conformational features of the resulting peptides 3 and 4 were studied by NMR, IR, and molecular modeling techniques. The presence of a reverse turn conformation was observed in all the structures, suggesting the key role of the scaffolds as reverse turn promoters. Peptides 3 and 4 did not adopt a preferred conformation as indicated by the presence of equilibria between open turn and intramolecular hydrogen-bonded structures. 6-endo-BTL-peptide 3 showed a 3:1 mixture of conformers. The major conformer adopted mainly an open turn structure in equilibrium with hydrogen-bonded structures. The minor conformer displayed a better organized structure with a 14-membered ring hydrogen-bond typical of a beta-hairpin-like structure, in equilibrium with a gamma-turn, too. 6-endo-BtL-peptide 4 showed a unique conformer, and did not adopt as good a conformation as 3, due to the bulky equatorial substituent at C-2. Thus, marked structural differences between peptides containing 6-endo-BTL and 6-endo-BtL scaffolds as reverse turn inducers exist.     

Thermolysis of vic-dihydroxybacteriochlorins: effect of the nature of substrates in directing the formation of chlorin-chlorin dimers with fixed and flexible orientations and their preliminary in vitro photosensitizing efficacy

The thermolysis products obtained by refluxing a series of vic-dihydroxychlorins in o-dichlorobenzene are characterized. Depending on the nature of substrates, this methodology provides an access for novel carbon-carbon linked chlorin-chlorin dimers and chlorin-porphyrin dimers with fixed and flexible orientations. The configuration of the linkers in the symmetrical and unsymmetrical dimers was confirmed by extensive NMR (COSY, ROESY) and molecular modeling studies. The molecular modeling studies of the energy-optimized dimers with flexible orientation confirmed that one of the chlorin units of the dimeric structure is tilted toward the opposite ring as evident by the shielding effect in the resonances of some of the protons in the (1)H NMR spectroscopy. Among the dimers with fixed orientation, compared to the free-base analogues, the related mono- and di-Zn(II) complexes produced a decreased fluorescence intensity, suggesting a possibility of the faster energy transfer via intersystem crossing (ISC) in the metalated derivatives than the corresponding free-base analogues to produce the corresponding excited triplet states. The photosensitizing efficacy of the monomers and the related dimers was also compared in radiation-induced fibrosarcoma (RIF) tumor cells at variable drug/light doses. In preliminary screening, compared to monomers, the corresponding carbon-carbon linked dimers produced enhanced photosensitizing efficacy.