Study of Host-Guest Complexation of Alkaline Earth Metal Ion,Aluminum Ion and Transition Metal Ions with Crown Ethers by Fast Atom Bombardment Mass Spectrometry

Complexations of crown ethers with alkali metal ions have been investigated extensively by FAB mass spectrometry over the past decade, but very little attention has been paid to reactions of crown ethers with other classes of metal ions such as alkaline earth metal ions, transition metal ions and aluminum ions. Although fast atom bombardment ionization mass spectrometry has proven to be a rapid and convenient method to determine the binding interactions of crown ethers with metal ions, problems in reliabilities for quantitative measurements of” binding strength for the host-guest complexes have been described in the literature. Thus, in this paper, applications of FAB/MS for investigating the complexation of crown ethers with various classes of metal ions is discussed. Extensive fragmentations for neutral losses such as C₂H₄O or C₂H₄ molecules from the host-guest complexes could be observed. The reason is attributed to the energetic bombardment processes of FAB occuring in the formation of these complexes. Complexes of cyclen with metal ions also show neutral losses of C₂H₄NH molecules leading to fragment ions. Transition metal ions usually form (Crown + MCl)⁺ type of ions, alkaline earth metal ions can form both (Crown + MCl)⁺ and (Crown + MOH)⁺ type of ions. But for aluminum ions, only (Crown + Al(OH)₂)⁺ type of ions could he observed.     

Determination of binding selectivities in host-guest complexation by electrospray/quadrupole ion trap mass spectrometry

The quantifiable relationship between the equilibrium solution composition and electrospray (ESI) mass spectral peak intensities of simple host-guest complexes was investigated. Specifically, host-guest complexes of simple crown ethers or glymes with alkali metals and ammonium ions were studied. Comparisons were made between the theoretical concentrations of host-guest complexes derived in solution from known stability constants and the peak intensities for the complexes observed by ESI mass spectrometry (ESI-MS). Two types of complexation experiments were undertaken. First, complexation of a single guest ion, such as an alkali metal, and two crown ethers was studied to evaluate the determination of binding selectivities. Second, complexation of two different guest ions by a single polyether host was also examined. In general, solvation was found to play an integral part in the ability to quantify binding selectivities by ESI-MS. The more similar the solvation energies of the two complexes in the mixture, the more quantifiable their binding selectivities by ESI-MS. In some cases, excellent correlation was obtained between the theoretically predicted selectivity ratios and the ESI mass spectral ratios, in particular when the ESI ratios were adjusted based on evaluation of ESI response factors for the various host-guest complexes.     

Host-guest complexes of crown ethers with HN-proton-donor molecules

Crown ethers were reacted with HN-proton-donor molecules to obtain crystalline molecular host-guest complexes. It was found that complexes with crown ethers of different structure are formed, depending on the linear dimensions and mode of steric shielding of active centers of the proton-donor molecules.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 12, 2004, pp. 2030–2033.Original Russian Text Copyright © 2004 by Wang, Ganin.This revised version was published online in April 2005 with a corrected cover date.     

新型蒽并冠醚的合成及主客体键合行为

以9,10-二溴甲基蒽为原料,经过3步反应合成了2种新型蒽并冠醚;采用核磁共振波谱、紫外光谱和单晶X射线衍射等手段研究了蒽并冠醚与2种π-缺电子客体之间的键合行为.结果表明,蒽并冠醚与客体之间的键合作用主要是π-堆积作用.通过紫外光谱滴定法测得蒽并冠醚与客体之间的键合常数高于经典的苯并冠醚和萘并冠醚,表明蒽结构基团的引入改善了冠醚的主-客体键合能力.     

Controllable macrocyclic supramolecular assemblies in aqueous solution

A series of macrocycles, including crown ethers, cyclodextrins, calixarenes, pillararenes and cucurbiturils, are well known to be able to associate various organic/inorganic/biological guest molecules and ions in their well-defined cyclic cavities to form stable host-guest complexes and supramolecular systems through the cooperative contributions of various non-covalent interactions. When one or more functional groups are attached to the cavity of macrocycles or guest molecules, enhanced and/or controlled host-guest associations may take place, leading to not only improved host-guest binding abilities but also fascinating properties. In this review, some representative contributions in the construction of controllable macrocyclic supramolecular assemblies in aqueous solution are presented with an emphasis on the stimuli-responsive control manner and wide applications of this property.     

Direct quantitation of active ingredients in solid artesunate antimalarials by noncovalent complex forming reactive desorption electrospray ionization mass spectrometry

The direct quantitation of active ingredients in solid pharmaceutical tablets by desorption electrospray ionization mass spectrometry (DESI MS) is complicated by the dependence of the DESI signal on variables such as spray angles and distances, morphological sample properties, and the difficulty of properly incorporating an internal standard. Here, a DESI MS method for the direct quantitative screening of widely counterfeited antimalarial tablets containing artesunate is presented. This method is based on reactive DESI, where analyte desorption and ionization occur by the formation of noncovalent complexes between alkylamine molecules in the DESI spray solution and artesunate molecules exposed on the sample surface in the open air. For quantitation purposes, the internal standard d4-artesunic acid was synthesized by esterification of d4-succinic anhydride and dihydroartemisinin, and homogeneously dispersed on the tablet surface via a controlled deposition procedure. The analyte-to-internal standard signal intensity ratio was observed to be largely independent of all DESI variables, only showing dependence on tablet hardness. Analysis of artesunate tablet standards prepared with known amounts of the active ingredient in the 0.02 to 0.32 mg artesunate mg(-1) tablet range resulted in a calibration curve with good linearity (r = 0.9985). Application of this method to the direct quantitation of genuine artesunate tablets from Vietnam showed a 6% (n = 4) precision and 94% accuracy after the spectral data were corrected for tablet hardness.     

Sugar‐Based Synthesis of Tamiflu and Its Inhibitory Effects on Cell Secretion

Tamiflu is currently the most effective drug for the treatment of influenza, but the insufficient supply and side‐effects of this drug demand urgent solutions. We present a practical synthesis of Tamiflu by using novel synthetic routes, cheap reagents, and the abundantly available starting material D ‐glucal. The strategy features a Claisen rearrangement of hexose to obtain the cyclohexene backbone and introduction of diamino groups through tandem intramolecular aziridination and ring opening. In addition, this synthetic protocol allows late‐stage functionalization for the flexible synthesis of Tamiflu analogues. By using the synthesized Tamiflu and its active metabolite (oseltamivir carboxylate), we investigated their influences on neuroendocrine PC12 cells in various aspects. It was discovered that oseltamivir carboxylate significantly inhibits the vesicular exocytosis (regulated secretion) of PC12 cells, and suggests a mechanism underlying the Tamiflu side‐effects, in particular its possible adverse influences on neurotransmitter release in the central nervous system.     

Enantiomeric recognition of amino acids by amphiphilic crown ethers in Langmuir monolayers

Four new chiral, amphiphilic crown ethers differing by the hydrophobic tailgroups were synthesized, and their capacity to recognize enantiomeric amino acids was examined using Langmuir films. Surface pressure and surface potential measurements performed on the subphases containing L or D enantiomers of alanine, valine, phenylglycine, and tryptophane indicate that the crown ethers forming the monolayer interact with the amino acids. The effects observed are ascribed to the formation of host-guest complexes. The differences in the magnitude of the effects measured show that the crown ethers are capable of discriminating between different amino acids as well as the enantiomers. Our results demonstrate that the structure of the monolayer plays a decisive role in the molecular recognition process including chiral recognition.     

酰胺型开链冠醚稀土配合物的超声化学合成

用声化学方法合成了八种新的酰胺型开链冠醚稀土配合物,经元素分析,IR,NMR,ES－MS表征,确定了配合物的组成,研究了它们的荧光性质。     

Rapid analysis of controlled substances using desorption electrospray ionization mass spectrometry

The recently developed technique of desorption electrospray ionization (DESI) has been applied to the rapid analysis of controlled substances. Experiments have been performed using a commercial ThermoFinnigan LCQ Advantage MAX ion-trap mass spectrometer with limited modifications. Results from the ambient sampling of licit and illicit tablets demonstrate the ability of the DESI technique to detect the main active ingredient(s) or controlled substance(s), even in the presence of other higher-concentration components. Full-scan mass spectrometry data provide preliminary identification by molecular weight determination, while rapid analysis using the tandem mass spectrometry (MS/MS) mode provides fragmentation data which, when compared to the laboratory-generated ESI-MS/MS spectral library, provide structural information and final identification of the active ingredient(s). The consecutive analysis of tablets containing different active components indicates there is no cross-contamination or interference from tablet to tablet, demonstrating the reliability of the DESI technique for rapid sampling (one tablet/min or better). Active ingredients have been detected for tablets in which the active component represents less than 1% of the total tablet weight, demonstrating the sensitivity of the technique. The real-time sampling of cannabis plant material is also presented.     

Improved desorption electrospray ionization mass spectrometry performance using edge sampling and a rotational sample stage

The position of the surface to be analyzed relative to the sampling orifice or capillary into the mass spectrometer has been known to dramatically affect the observed signal levels in desorption electrospray ionization mass spectrometry (DESI‐MS). In analyses of sample spots on planar surfaces, DESI‐MS signal intensities as much as five times greater were routinely observed when the bottom of the sampling capillary was appropriately positioned beneath the surface plane (‘edge sampling’) compared with when the capillary just touched the surface. To take advantage of the optimum ‘edge sampling’ geometry and to maximize the number of samples that could be analyzed in this configuration, a rotational sample stage was integrated into a typical DESI‐MS setup. The rapid quantitative determination of caffeine in two diet sport drinks spiked with an isotopically labeled internal standard demonstrated the utility of this approach. Published in 2008 by John Wiley & Sons, Ltd.     

Stabilization of germanium(IV) aquafluorocompounds in host-guest type complexes with crown ethers. synthesis,crystal structure and ir spectra of the complexes [(GeF5-H2O)2-(H2-1,10-Diaza-l 8-Crown-6)] and [(trans-GeF4 · 2H2O) · 18-Crown-6·2H2O]

Stable products have been obtained from the interaction of GeO₂-HF solution with 18-membered crown ethers, 1,10-diaza-l8-crown-6 and 18-crown 6. Complexes were characterized by X-ray analysis and IR spectroscopy. Both Ge(IV) aquafluorocompounds are isostructural with their Si analogues. It was established that in the host-guest type complexes the germanium moiety as a central atom has been stabilized in the form of octahedral complexes. The host-guest interaction occurs by means of O-H(W)...O_cr, OH...F and N-H...F hydrogen bonds.     

Analysis of sexual assault evidence: statistical classification of condoms by ambient mass spectrometry

Desorption electrospray ionization mass spectrometry (DESI‐MS) and easy ambient sonic‐spray ionization mass spectrometry (EASI‐MS) are employed here in the forensic analysis of chemical compounds found in condoms and relative traces, and their analytical performances are compared. Statistical analysis of data obtained from mass spectra only was applied in order to obtain classification rules for distinguishing ten types of condoms. In particular, two supervised chemometric techniques [linear discriminant analysis (LDA) and soft independent modeling of class analogy (SIMCA)] were carried out on absolute and relative intensity values to test the performances of statistical models in terms of predictive capacity. The achieved classification of samples was excellent because of the high prediction percentages of the method used both for DESI and EASI mass spectrometry analyses, confirming these two as potential ambient ionization techniques for forensic analyses in case of sexual assault crimes. EASI‐MS showed 99% prediction ability for LDA using relative data and 100% prediction ability for SIMCA using both absolute and relative ones, while DESI showed 94% prediction ability for both LDA and SIMCA. The absence of any sample preparation technique gives advantages in terms of sample preservation and reduced contamination, allowing successive analyses to be performed on the same sample by other techniques. Copyright © 2015 John Wiley & Sons, Ltd.     

Prediction of Complexation Properties of Crown Ethers Using Computational Neural Networks

A computational neural network method was used for the prediction of stability constants of simple crown ether complexes. The essence of the method lies in the ability of a computer neural network to recognize the structure-property relationships in these host-guest systems. Testing of the computational method has demonstrated that stability constants of alkali metal cation (Na+, K+, Cs+)-crown ether complexes in methanol at 25 °C can be predicted with an average error of ±0.3 log K units based on the chemical structure of the crown ethers alone. The computer model was then used for the preliminary analysis of trends in the stabilities of the above complexes.     

Double armed crown ethers and armed macrocycles as a new series of metal-selective reagents: a review

Various double armed crown ethers and related macrocycles are presented as metal-selective reagents characterized by macrocyclic ligands and metal-ligating sidearms. They exhibit unique metal binding and recognition functions via macroring-sidearm cooperative action. Since they form three dimensional complexes suitable for metal-sensing and separation, we can develop a new series of metal-selective reagents via armed macrocycle strategy. Polymerization and immobilization of the armed macrocycles further enhance the usefulness in analytical science. This review focuses primarily on the molecular design, host-guest chemistry, and analytical applications of the armed macrocycles, and clearly indicates that these macrocycles provide new options in designing a metal-selective reagent.     

Ethylenediamine as a liquid chemical reagent to probe hydrogen bonding and host-guest interactions with crown ethers in an ion trap tandem mass spectrometer

Ethylenediamine (EDA) was used as a novel liquid chemical reagent to probe hydrogen bonding and host-guest interactions with crown ether derivatives in an ion trap mass spectrometer (ITMS). Selective ion/molecule reaction product ions were generated by reactions of EDA with oxygenated and aza-crown ethers. For the oxygenated crown ethers, glycols and dimethylglycols, ion/molecule reactions led to the formation of the protonated molecules ([M+H](+)) and adduct ions including [M+30](+), [M+44](+) and [M+61](+). The aza-crown ethers produced [M+H](+), [M+13](+) and [M+27](+) ions. Collisionally activated dissociation (CAD) experiments were applied to probe the binding strength of these ion/molecule reaction products. CAD results indicated that all these hydrogen-bonding complexes are weakly bound except for the [M+44](+) ion of 18-crown-6, since all the complexes dissociate to the protonated polyether and/or protonated EDA. Fragmentation of the [M+H](+) ions under CAD conditions indicates the extensive covalent bond cleavage of the protonated crown ether skeleton.     

Native Desorption Electrospray Ionization Liberates Soluble and Membrane Protein Complexes from Surfaces

Mass spectrometry (MS) applications for intact protein complexes typically require electrospray (ES) ionization and have not been achieved via direct desorption from surfaces. Desorption ES ionization (DESI) MS has however transformed the study of tissue surfaces through release and characterisation of small molecules. Motivated by the desire to screen for ligand binding to intact protein complexes we report the development of a native DESI platform. By establishing conditions that preserve non‐covalent interactions we exploit the surface to capture a rapid turnover enzyme–substrate complex and to optimise detergents for membrane protein study. We demonstrate binding of lipids and drugs to membrane proteins deposited on surfaces and selectivity from a mix of related agonists for specific binding to a GPCR. Overall therefore we introduce this native DESI platform with the potential for high‐throughput ligand screening of some of the most challenging drug targets including GPCRs.     

Direct analysis of liquid samples by desorption electrospray ionization-mass spectrometry (DESI-MS)

Desorption electrospray ionization-mass spectrometry (DESI-MS) was evaluated for the direct analysis of liquid samples. Several interesting results were found. First, in contrast to the previous DESI analysis of dried solid samples that was limited to proteins with MW ≤25 kDa (Anal. Chem. 2007, 79, 3514), bovine serum albumin (BSA, 66 kDa) was successfully ionized from solutions by DESI with observation of corresponding multiply charged ions. Second, direct DESI analysis of protein tryptic digest solutions without chromatographic separation, sample clean-up, and the sample drying step was demonstrated, providing reasonably good sequence coverage of 52% to 97%. Third, direct analysis of biofluids such as an undiluted urine sample without sample pretreatment is possible, emphasizing the high tolerance of DESI with salt. These results suggest that a charged droplet pick-up mechanism is responsible for desorption and ionization of liquid samples by DESI. Also, unlike in electrospray ionization (ESI), inhibition of electrochemical reduction in the negative ion mode was observed for liquid sample DESI. In addition, reactive DESI can be performed with ion/ion reactions of Zn(II) complexes for the selective binding of phosphoserine in the presence of serine. DESI experiment can also be carried out directly to liquid samples flowing out of a pumped syringe needle tip, allowing rapid analysis. Furthermore, on-line coupling of electrochemical cell with DESI-MS was demonstrated, in which perylene radical cations generated in the cell were successfully transferred to the gas-phase for MS detection by DESI. This study extended the scope of DESI-MS applications, which could have potentials in bioanalytical and forensic analysis.     

Second-Sphere Coordination of Ferrioxamine B and Association of Deferriferrioxamine B, CH(3)(CH(2))(4)NH(3)(+), NH(4)(+), K(+), and Mg(2+) with Synthetic Crown Ethers and the Natural Ionophores Valinomycin and Nonactin in Chloroform

The interaction of ferrioxamine B, FeHDFB(+), through a protonated amine side chain, with various host ionophore structures to form a host-guest complex in the second coordination shell has been investigated. Host-guest association constants (K(a)) in water saturated chloroform are reported for synthetic crown ethers with different cavity size and substituents (18-crown-6 and its dicyclohexano, benzo, and dibenzo derivatives; dibenzo and dicyclohexano derivatives of 24-crown-8; and dibenzo-30-crown-10). The natural ionophores valinomycin and nonactin were also found to form stable second-sphere complexes with ferrioxamine B in wet chloroform. Results are reported for both picrate and perchlorate salts of FeHDFB(+). Since the protonated amine side chain of ferrioxamine B may be viewed as a substituted amine, the host-guest association constants for FeHDFB(+) are compared to the interaction of Mg(2+), K(+), NH(4)(+), CH(3)(CH(2))(4)NH(3)(+), and H(4)DFB(+) with the same ionophores. This is the first report of nonactin complexation of this series of cations in an organic medium of low polarity and one of the few reports of valinomycin complexation. To the best of our knowledge these are the first reported stability constants for the association of (Mg(2+),2pic(-)) with natural and synthetic ionophores in chloroform. K(a) values for ferrioxamine B complexation by the synthetic crown ethers are influenced by ring size and substituent. Despite significant preorganization capabilities, the large cavities of valinomycin, nonactin and benzo-30-crown-10 do not form as stable host-guest assemblies with bulky substituted amine cations such as ferrioxamine B as does cis-dicyclohexano-18-crown-6.     

Design and synthesis of immobilized Tamiflu analog on resin for affinity chromatography

A resin linked with the Tamiflu core was synthesized by modifying our original synthetic route of oseltamivir phosphate (Tamiflu). The prepared resin bound to the influenza virus enzyme neuraminidase, the main target of Tamiflu. The immobilized Tamiflu analog will be useful for isolating and identifying presumed endogenous vertebrate proteins that interact with Tamiflu, which might relate to the abnormal behavior exhibited by some influenza patients treated with Tamiflu.