d-Xylose-based surfactants: Synthesis,characterization and molecular modeling studies

Pentose-derived surfactants were easily synthesized and fully characterized through classical analytical methods. The interfacial behaviors revealed the importance of both the length of the hydrophobic chain and the nature of the anomeric form. Finally, the spatial conformation of four xylosides was obtained by molecular modeling with software Hyperchem^® 4 using the semi-empirical method PM3, which demonstrated the role of hydrophobic interactions in the stability of the compounds.     

Fragmentation studies on lasalocid acid by accurate mass electrospray mass spectrometry

Lasalocid acid is an important polyether ionophore veterinary drug. Polyether ionophores have been the subject of MS study for many years, but this is the first rigorous study of the complex fragmentation processes occurring in ESI MS/MS for lasalocid, underpinned by high-resolution accurate-mass measurement. Initial low-resolution analyses were performed on an ion-trap instrument. High-resolution analyses were performed on a Fourier-transform ion cyclotron resonance mass spectrometer. The MS/MS analysis of the pseudo-molecular ion shows that fragment ions are produced either by beta-elimination or by neutral losses of water. Additional ions were observed in the source dissociation analysis, indicating that additional fragmentation reactions occur in the source region. Some of these ions can then undergo additional ion-ion or ion-molecule reactions before being extracted from the source. The study of both the protonated and sodiated sodium salts shows the same fragmentation pathways, with fragment ions containing two sodiums at low intensity. A fragmentation pathway of the lasalocid acid protonated sodium salt [(M-H+Na)+H]+ (m/z 613) and sodiated sodium salt [(M-H+Na)+Na]+ (m/z 635) is presented. The increased understanding afforded by this study will help in the development of unequivocal analytical methods for lasalocid and related polyether ionophore veterinary drugs.     

Matrix-assisted laser desorption/ionization mass spectrometry, enzymatic digestion, and molecular modeling in the study of nonenzymatic glycation of IgG

The glycation-induced functional change of immunoglobulins is of particular interest. The glycation levels of IgG in 10 healthy subjects and 20 diabetic patients with different degrees of metabolic control were studied by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. It reveals the number of glucose molecules that have condensed on the protein, which range from 1 to 5 for healthy subjects, from 5 to 9 for well controlled diabetic patients, and from 10 to 25 for poorly controlled ones. The identification of the most favored glycation sites has been obtained by MALDI analysis of standard and in vitro glycated IgG and plasma protein fraction of a healthy subject after digestion with papain, releasing Fab and Fc fragments of the molecule. Both experiments, as well as molecular modeling of the whole protein, confirm that the most of glucose molecules have condensed on the Fab fragment of IgG, suggesting that the immune deficiency observed in diabetic patients may be explained at the molecular level by a more effective glycation of the Fab fragment, thus inhibiting the process of molecular recognition between antibody and antigen.     

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry studies of low molecular weight dendrimers

We report the application of matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry, with delayed extraction in the reflectron mode, for the characterization of low molecular weight dendrimers. 20 dendrimer samples were measured and 4 typical dendrimers, as examples, are discussed in detail. Several factors that affect the analysis including the matrices used, the concentrations of sample, the solvents and cationization reagent used, were investigated in detail. Experimental results indicate that the type of solvent can greatly influence exact mass measurement. However, sample preparation is generally not very critical for dendrimer analysis using MALDI-ToF since many kinds of matrices and a wide range of sample concentrations can be used efficiently. In addition, the Cs(+) ion can be used to enhance the efficiency of cationization. Some reasons for this behavior are discussed on the basis of results of calculations using Gaussian94 software (a connected system of programs for performing a variety of semi-empirical and ab initio molecular orbital (MO) calculations).     

Desorption electrospray ionisation mass spectrometry and tandem mass spectrometry of low molecular weight synthetic polymers

A range of low molecular weight synthetic polymers has been characterised by means of desorption electrospray ionisation (DESI) combined with both mass spectrometry (MS) and tandem mass spectrometry (MS/MS). Accurate mass experiments were used to aid the structural determination of some of the oligomeric materials. The polymers analysed were poly(ethylene glycol) (PEG), polypropylene glycol (PPG), poly(methyl methacrylate) (PMMA) and poly(alpha-methyl styrene). An application of the technique for characterisation of a polymer used as part of an active ingredient in a pharmaceutical tablet is described. The mass spectra and tandem mass spectra of all of the polymers were obtained in seconds, indicating the sensitivity of the technique.     

Electrospray mass spectrometry and molecular modeling study of formation and stability of silver complexes with diazaperylene and bisisoquinoline

The complex formation of the following diazaperylene ligands (L) 1,12‐diazaperylene 1 , 1,1′‐bisisoquinoline 2 , 2,11‐disubstituted 1,12‐diazaperylenes (alkyl = methyl, ethyl, isopropyl, 3 , 5 , 7 ), 3,3′‐disubstituted 1,1′‐bisisoquinoline (alkyl = methyl, ethyl, isopropyl, 4 , 6 , 8 and with R = phenyl, 11 and with pyridine 12 ), and the 5,8‐dimethoxy‐substituted diazaperylene 9 , 6,6′‐dimethoxy‐substituted bisisoquinoline 10 with AgBF4 was investigated. Collision‐induced dissociation measurements were used to evaluate the relative stabilities of the ligands themselves and for the [1:1]⁺ complexes as well as for the homoleptic and heteroleptic silver [1:2]⁺ complexes in the gas phase. This method is very useful in rapid screening of the stabilities of new complexes in the gas phase. The influence of the spatial arrangement of the ligands and the type of substituents employed for the complexation were examined. The effect of the preorganization of the diazaperylene on the threshold activation voltages and thus of the relative binding energies of the different complexes are discussed. Density functional theory calculations were used to calculate the optimized structures of the silver complexes and compared with the stabilities of the complexes in the gas phase for the first time.     

Reaction of naphthalene-2,3-dicarboxaldehyde with enkephalins for LC-fluorescence and lc-ms analysis: Conformational studies by molecular modeling and H/D Exchange mass spectrometry

A new labeling method compatible with both laser-induced fluorescence (LIF) and MS detection for enkephalins, which uses naphthalene-2,3-dicarboxaldehyde (NDA) and a new nucleophilic agent (N,N-dimethylaminoethanethiol) is described. When the derivative is separated via reverse phase HPLC and detected via MS, two different peaks with similar exact mass but different fluorescence and fragmentation properties are obtained. To interpret these results, molecular modeling and H/D exchange mass spectrometry studies were investigated to test the hypothesis that the peak obtained by LC/LIF/MS analysis depends on the site of protonation of the labeled enkephalins. The peptides labeled with NDA and N,N-dimethylaminoethanethiol were separated on a reverse phase C18 column with a gradient of aqueous 0.1% formic acid and acetonitrile. In mass spectrometry, two peaks are observed with the same exact mass for each molecule while only one peak is detected using fluorescence. Tandem mass spectrometry experiments of ion m/z 809.5 were performed on each chromatographic peak; the first peak (which is not observed by LIF detection) gives a fragment corresponding to the loss of the aminothiol side chain while no fragmentation is observed on the second peak, which was detected by fluorescence. The hypothesis is that each peak represents the labeled enkephalin with different sites of protonation. According to this hypothesis, three fundamental conformations that were closed to the unlabeled leucine-enkephalin were obtained by molecular modeling: a beta-turn like conformation with two hydrogen bonds, a 3(10)-helix with an H bond, and finally, the extended form without any intramolecular interactions. H/D exchange mass spectrometry experiments with D(2)O and d(2-)formic acid as eluent was used to determine which conformation is involved in each peak.     

Novel lithocholaphanes: Syntheses, NMR, MS, and molecular modeling studies

Novel head-to-head lithocholaphanes 6 and 11 have been synthesized via precursors 1–5 and 7–10 with overall good yields, and characterized by ¹H, ¹³C, and ¹⁵N NMR spectroscopy, ESI-TOF mass spectrometry, thermal analysis, and molecular modeling. In addition, the binding abilities of 6 and 11 towards alkali metal cations have been investigated via competitive complexation studies using equimolar mixtures of Li⁺, Na⁺, K⁺, and Rb⁺-cations, and cholaphanes 6 and 11. The formation of cation–cholaphane adducts was detected by ESI-TOF mass spectrometry. The trends in these comparative binding studies are nicely reproduced theoretically with PM3 energetically optimized structures of 6 and 11 and their interaction energies with alkali metal cations calculated by molecular mechanics. Cholaphane 11 possessing a peptoid type structural fragment, –(CH₂CONHCH₂CH₂)₂O–, as a coordination sphere, shows binding tendency towards lithium and sodium cations, whereas 6 possessing an ester type, –(CH₂OCOCH₂)₂O–, moiety and a bigger cavity size than 11, shows merely a tendency towards bigger alkali metal cations, potassium and rubidium.     

Ligand binding mode to duplex and triplex dna assessed by combining electrospray tandem mass spectrometry and molecular modeling

In this paper, we report the analysis of seven benzopyridoindole and benzopyridoquinoxaline drugs binding to different duplex DNA and triple helical DNA, using an approach combining electrospray ionization mass spectrometry (ESI-MS), tandem mass spectrometry (MS/MS), and molecular modeling. The ligands were ranked according to the collision energy (CE(50)) necessary to dissociate 50% of the complex with the duplex or the triplex in tandem MS. To determine the probable ligand binding site and binding mode, molecular modeling was used to calculate relative ligand binding energies in different binding sites and binding modes. For duplex DNA binding, the ligand-DNA interaction energies are roughly correlated with the experimental CE(50), with the two benzopyridoindole ligands more tightly bound than the benzopyridoquinoxaline ligands. There is, however, no marked AT versus GC base preference in binding, as supported both by the ESI-MS and the calculated ligand binding energies. Product ion spectra of the complexes with triplex DNA show only loss of neutral ligand for the benzopyridoquinoxalines, and loss of the third strand for the benzopyridoindoles, the ligand remaining on the duplex part. This indicates a higher binding energy of the benzopyridoindoles, and also shows that the ligands interact with the triplex via the duplex. The ranking of the ligand interaction energies compared with the CE(50) values obtained by MS/MS on the complexes with the triplex clearly indicates that the ligands intercalate via the minor groove of the Watson-Crick duplex. Regarding triplex versus duplex selectivity, our experiments have demonstrated that the most selective drugs for triplex share the same heteroaromatic core.     

High-performance liquid chromatography-electrospray ionization mass spectrometry and multiple mass spectrometry studies of hyperforin degradation products

The alcoholic extract of the aerial parts of Hypericum perforatum L. finds wide application because of its antidepressant activity. The extract contains a number of constituents with documented biological activity including chlorogenic acid, a broad range of flavonoids, naphthodianthrones and phloroglucinols. Hyperforin and adhyperforin are the major phloroglucinol constituents found in the lipophilic fraction of the extracts. Since the stability of hyperforin has been shown to be limited, an investigation of the hyperforin degradation products using HPLC-electrospray ionization mass spectrometry and multiple mass spectrometry was undertaken.     

Thiol-functionalized anthraquinones: mass spectrometry and electrochemical studies

Abstract  

In this work, the synthesis of various thiol-functionalized anthraquinone compounds is presented. The studied compounds were characterized by mass spectrometry and the main fragmentation pathways are discussed. The compounds studied formed stable self-assembled monolayers (SAMs) in the gold surface. The parameters for the reduction processes in the gold surface of the studied new anthraquinones were determined by cyclic voltamperometry tests.     

Investigations on cluster and molecular ion formation by plasma mass spectrometry

The formation of molecular and cluster ions of different inorganic materials in plasma mass spectrometry – spark source mass spectrometry (SSMS), radiofrequency glow discharge mass spectrometry (rf GDMS), laser ionization mass spectrometry (LIMS), inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS (LA-ICP-MS) – was investigated and compared. Similar abundance distributions of cluster ions were observed for a graphite sample, for boron nitride/ graphite and for metal oxide/graphite mixtures using different plasma mass spectrometric methods. A correlation of intensities of metal argide ions in ICP-MS with their bond dissociation energies was used to estimate unknown dissociation energies of molecular ionic species. For the elements of the 2nd or 3rd period in the periodic table, the intensities of most argon molecular ions (ArX⁺) measured by ICP-MS rise with increasing atomic number in a similar manner to the theoretically calculated bond dissociation energies of argon molecular ions.     

Pharmacophore modeling,atom based 3D-QSAR,molecular docking and molecular dynamics studies on Escherichia coli ParE inhibitors

ATP dependent ParE enzyme is as an attractive target for the development of antibacterial agents. Atom based 3D-QSAR model AADHR.187 was developed based on the thirty eight Escherichia coli ParE inhibitors. The generated model showed statistically significant coefficient of determinations for the training (R² = 0.985) and test (R² = 0.86) sets. The cross-validated correlation coefficient (q2) was 0.976. The utility of the generated model was validated by the enrichment study. The model was also validated with structurally diverse external test set of ten compounds. Contour plot analysis of the generated model unveiled the chemical features necessary for the E. coli ParE enzyme inhibition. Extra-precision docking result revealed that hydrogen bonding and ionic interactions play a major role in ParE protein-ligand binding. Binding free energy was computed for the data set inhibitors to validate the binding affinity. A 30-ns molecular dynamics simulation showed high stability and effective binding of inhibitor 34 within the active site of ParE enzyme. Using the best fitted model AADHR.187, pharmacophore-based high-throughput virtual screening was performed to identify virtual hits. Based on the above studies three new molecules are proposed as E. coli ParE inhibitors with high binding affinity and favourable ADME properties.