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Quinine as a highly responsive chiral sensor for the 1H and 19F NMR enantiodiscrimination of N-trifluoroacetyl amino acids with free carboxyl functions
No full textHydrogen-bond accepting and enantiodiscriminating abilities of quinine (Qui) have been exploited in the enantiodiscrimination of N-trifluoroacetyl (TFA) derivatives of amino acids by NMR (NMR) spectroscopy. NMR 1H and 19F resonances of derivatives of alanine, valine, leucine, norvaline, phenylalanine, phenylglycine, methionine, glutamic acid, proline, and tryptophan were well differentiated employing CDCl3 and/or C6D6 as solvent, with Qui acting in some cases not only as enantiodiscriminating agent, but also as solubility promoter. For derivatives soluble in both solvents, the best results were obtained in benzene-d6, with very high nonequivalence values, which were detectable not only starting from very low equimolar concentrations of 0.1 mM, but also in the presence of sub-stoichiometric amounts of Qui. The quality of enantiodifferentiation has been also evaluated by means of the enantioresoln. quotient E. The method has been applied to the detection and quantification of mixtures of amino acid derivatives by single point measurements
Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid Derivatives
Get PDF[Image: see text] A C2-symmetrical bis-thiourea chiral solvating agent (CSA), TFTDA, for NMR spectroscopy has been obtained by reacting (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3,5-bis(trifluoromethyl)phenyl isothiocyanate. TFTDA shows remarkable propensity to enantiodiscriminate N-trifluoroacetyl (N-TFA) and N-acetyl (N-Ac) derivatives of amino acids with free carboxyl functions, with the co-presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the third achiral additive, which is needed for substrate solubilization. TFTDA shows enhanced enantiodiscriminating efficiency in comparison with the corresponding monomeric counterpart, TFTMA, pointing out cooperativity between its two symmetrical entities. A wide range of amino acid derivatives have been efficiently enantiodiscriminated in CDCl(3), with high enantioresolution quotients, which guarantee high quality in applications devoted to the quantification of enantiomers. High enantiodiscriminating efficiency is maintained also in diluted 5 mM conditions or in the presence of sub-stoichiometric amounts of CSA (0.3 equiv). The role of phenolic hydroxyls in the DABCO-mediated interaction mechanism between TFTDA and the two enantiomeric substrates has been pointed out by means of diffusion-ordered spectroscopy (DOSY) and rotating frame Overhauser effect spectroscopy (ROESY) experiments. A conformational model for both the CSA and its diastereomeric solvates formed with the two enantiomers of N-acetyl leucine has also been conceived on the basis of ROE data in order to give a chiral discrimination rationale
Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics
Get PDFSilylated-acetylated cyclodextrin (CD) derivatives have recently been investigated, via nuclear magnetic resonance (NMR) spectroscopy, as chiral sensors for substrates that are endowed and devoid of fluorine atoms, and the importance of Si-F interaction in the discrimination phenomena has been assessed. Here, the contributions of both superficial interactions and inclusion processes were further evaluated by extending the records to other chiral fluorinated substrates of interest for pharmaceutical applications. Non-equivalences were measured for both the 1H and 19F resonances in equimolar mixtures with the CDs; the promising results also supported the use of chiral sensors in sub-stoichiometric amounts. Finally, the occurrence of inclusion processes was evaluated by analyzing the intermolecular dipolar interactions by means of ROESY (Rotating-frame Overhauser Enhancement Spectroscopy) experiments. The study confirmed that the γCD derivative is the best chiral solvating agent for the fluorinated substrates investigated, likely due to the higher number of silyl moieties that can be involved in Si-F interactions. The contribution of inclusion processes to the enantiodiscrimination was also confirmed by comparison with the α- and β-analogues. Overall, the CD derivatives proved to be able to discriminate fluorinated substrates even when used in sub-stoichiometric amounts
NMR Investigation of the Interaction of Three Non-Steroidal Anti-Inflammatory Drugs with Human Serum Albumin
Get PDFThe understanding of the interaction between non-steroidal anti-inflammatory drugs and human serum albumin plays a fundamental role in the development of new drugs and new therapeutic strategies. Several studies have been performed, nevertheless, the interaction phenomena are still not fully understood. In this work, high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy was applied to compare the strength of the interaction of diclofenac sodium salt, ketorolac tris salt and flurbiprofen sodium salt toward albumin. To this aim, mono- and bi-selective relaxation rate measurements were performed by applying selective π-pulses at the selected frequencies and by following magnetization recovery. On the basis of the dependence of relaxation parameters on albumin concentration, normalized affinity indexes were calculated for several protons of the drugs. Affinity indexes for diclofenac were about five-fold higher in comparison with ketorolac and flurbiprofen. Aromatic moieties of the three drugs and methine protons at the chiral centers of ketorolac and flurbiprofen were more involved in the interaction with albumin. In conclusion, NMR spectroscopy allows not only for the comparison of drug-to-protein affinities but also points out the nature of the drug sites that are more extensively involved in the interaction
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Coniugati ammonio-chitosani modificati con ciclodestrine: sintesi, caratterizzazione, affinità per la dalargina e sua idrolisi enzimatica da parte dell'α-chimotripsina. Uno studio di spettroscopia di risonanza magnetica nucleare (NMR)
No full textIl chitosano ammonio-coniugato (N+-Ch-CD), preparato da chitosano commerciale parzialmente depolimerizzato, è stato legato covalentemente alla 2-metil-β-ciclodestrina, utilizzando come spaziatore esametilene diisocianato. Il prodotto è stato caratterizzato tramite spettroscopia NMR, determinandone il contenuto di ciclodestrina (22%), di spaziatore (20%) e il peso molecolare (317000 g/mol).
È stata, poi, confrontata l’affinità della dalargina, principio attivo esapeptidico, per il polimero coniugato alla ciclodestrina, il polimero ammonio precursore, e la ciclodestrina stessa. A tale scopo sono stati utilizzati metodi di misura delle velocità di rilassamento protonico mono e bi-selettivo, che hanno rivelato la maggiore affinità della dalargina per il polimero covalentemente legato alla ciclodestrina rispetto agli altri sistemi.
Il polimero coniugato con la ciclodestrina si è anche dimostrato l’unico in grado di influenzare la velocità di idrolisi enzimatica della dalargina da parte
dell’α-chimotripsina.
Lo studio NMR dell’interazione della dalargina con la ciclodestrina, utilizzata come sistema modello, ha individuato nei raggruppamenti aromatici della dalargina le componenti molecolari del principio attivo prevalentemente coinvolte nell’interazione con la ciclodestrina, tramite processi di inclusione nella cavità idrofobica dell’oligosaccaride dal suo bordo di diametro maggiore
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Chiral analysis by NMR spectroscopy
No full textIn the present PhD project new chiral solvating agents (CSAs) have been proposed for the differentiation of enantiomers of chiral substrates by 1H/19F NMR spectroscopy, aimed to enantiomeric purity determinations. In order to investigate the interaction mechanisms on which chiral recognition relies, the stereochemical, dynamic and thermodynamic features of the diastereomeric complexes formed by each chiral receptor and selected enantiomeric substrates have been deeply investigated by means of ROESY and DOSY experiments, as well as by analysing the dependence of observed NMR spectral parameters on total concentration or substrate-to-CSA molar ratios.
CSAs belonging to the classes of polyamide systems, natural products, and macrocyclic receptors were selected.
Among polyamide CSAs, mono- and bis-thioureas have been taken into consideration. Mono-thioureas BTMA, BTMA1, BTMA2, BTMA3 and TFTMA were obtained by reacting the corresponding amine platforms 2‑[(1R)‑1-aminoethyl]phenol (MA), (1S,2R)-(−)-cis-1-amino-2-indanol (MA1), (1R,2R)-(−)-trans-1-amino-2-indanol (MA2) and (R)-1-phenylethylamine (MA3) with benzoyl isothiocyanate (BI) or 3,5-bis(trifluoromethyl)phenyl isothiocyanate (TFI). For the preparation of C2 symmetrical bis-thioureas BTDA and TFTDA, (1R,2R)-1,2-bis(2-hydroxyphenyl)ethylenediamine (DA) has been selected as amine precursor.
The two mono-thiourea CSAs with highest enantiodiscriminating efficiency have proven to be BTMA for the separation of N-dinitrobenzoyl (N-DNB) amino acid derivatives and TFTMA for N-acetyl (N-Ac) and N-trifluoroacetyl (N-TFA) amino acid derivatives. However, the corresponding bis-thiourea BTDA and TFTDA turned out to be increasingly more effective than their monomeric counterpart, leading to even higher differentiations of enantiomeric signals. For both dimeric systems, a cooperation between the two thiourea arms in the stabilization of diastereomeric solvates was pointed out.
In all cases, a strong base (DABCO/DMAP) was needed as solubilizer for amino acid derivatives with underivatized carboxyl functions. NMR investigations demonstrated that the base plays a key role also in the stabilization of diastereomeric complexes, by acting as a bridge in the interaction between CSA and two enantiomers. As well as it was ascertained that the phenolic hydroxyl of BTMA, TFTMA, BTDA and TFTDA participated to the tight network of hydrogen bond interactions substrate to CSA, favouring a syn/anti arrangement of the two thiourea NHs. Attractive π-π interactions involving the 2-hydroxyphenyl moiety of BTMA or BTDA and the 3,5-dinitrophenyl groups of N-DNB derivatives of amino acids contributed to the stabilization of the diastereomeric complexes formed in solution. 3,5-Bis(trifluoromethyl)phenyl moieties of TFTDA mainly acted on the acidity of the adjacent thiourea NH, boosting the hydrogen bond interactions between the CSA and enantiomers of N-Ac or N-TFA derivatives of amino acids, thus accounting for the different enantiodiscriminating features of the two kinds of thiourea CSAs.
In the field of natural products, we considered quinine (Qui) as possible multireceptorial chiral auxiliary endowed with a strong basic site, i.e. its quinuclidine nitrogen, in the NMR enantiodiscrimination of N-TFA amino acid derivatives. Qui produced particularly high 1H and 19F enantiomers differentiation in C6D6 (or CDCl3 for amino acids scarcely soluble in other solvents) also in sub-stoichiometric conditions of CSA. Qui was effective in the analysis of complex multicomponent mixtures and allowed very accurate enantiomeric purity determinations.
Derivatized cyclodextrins (CDs) were considered among macrocyclic receptor, for the NMR differentiation both of lipophilic and hydrophilic chiral substrates of pharmaceutical relevance. The three acetylated-silylated (α, β- and γ-AcSiCD) CDs effectively enantiodiscriminated chiral fluorinated compound B (COMP B) and methyl 2-chloropropanoate (MCP).
The greatest NMR enantioseparations were observed for COMP B and MCP in C6D12 by employing γ-AcSiCD and β-AcSiCD as chiral solvating agents, respectively. NMR mechanistic investigations demonstrated that, in the case of fluorinated chiral substrate, the enantiodiscrimination efficiency depends on deviations from truncated-cone shape structure of CDs, favouring attractive Si-F interactions at the external surface, rather than on the optimal fitting between the cavity of the cyclodextrin and the guest, leading to a non-deep inclusion of the guest. In that way the cyclodextrin having the greater number of glucopyranose rings, i.e. γ-AcSiCD, produces better enantiodiscrimination in comparison with β-AcSiCD, which forms the more stable diastereomeric solvates in virtue of the better size-fitting. On the contrary, MCP devoid of fluorinated groups is deeply included into the cyclodextrin and β-AcSiCD, giving the best fitting between the size of the cavity and the guest, shows greater enantiodiscriminating efficiency in comparison to γ-AcSiCD.
Among CD derivatives, also the partially and exhaustively methylated β-cyclodextrins were considered and compared in the enantiodiscrimination and in the hydrolysis of oxazepam hemisuccinate (OXM). The chemical stability of OXM over time as a pure compound and in the presence of β-CD, (2-methyl)-β-CD (MCD), heptakis(2,6-di-O-methyl)-β-CD (DIMEB) and heptakis(2,3,6-tri-O-methyl)-β-CD (TRIMEB) was evaluated, by monitoring the hydrolysis of the hemisuccinate chain. Among the methylated cyclodextrins, DIMEB has proven to be the most suitable to differentiate the two enantiomers of OXM, with high nonequivalences and complexation shifts, without producing hydrolysis of the hemisuccinate chain, which is mainly due to the presence of the cyclodextrin hydroxyls at the 2 and 6 positions
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