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Concept: NMR spectroscopy

175

Nuclear pore complexes form a selective filter that allows the rapid passage of transport factors (TFs) and their cargoes across the nuclear envelope, while blocking the passage of other macromolecules. Intrinsically disordered proteins (IDPs) containing phenylalanyl-glycyl (FG) rich repeats line the pore and interact with TFs. However, the reason that transport can be both fast and specific remains undetermined, through lack of atomic-scale information on the behavior of FGs and their interaction with TFs. We used NMR spectroscopy to address these issues. We show that FG repeats are highly dynamic IDPs, stabilized by the cellular environment. Fast transport of TFs is supported because the rapid motion of FG motifs allows them to exchange on and off TFs extremely quickly through transient interactions. Because TFs uniquely carry multiple pockets for FG repeats, only they can form the many frequent interactions needed for specific passage between FG repeats to cross the NPC.

Concepts: Pharmacology, Cell nucleus, Nuclear magnetic resonance, NMR spectroscopy, Interaction, Nuclear pore, Nuclear envelope, The Passage

149

Quinomycin G (1), a new analogue of echinomycin, together with a new cyclic dipeptide, cyclo-(l-Pro-4-OH-l-Leu) (2), as well as three known antibiotic compounds tirandamycin A (3), tirandamycin B (4) and staurosporine (5), were isolated from Streptomyces sp. LS298 obtained from a marine sponge Gelliodes carnosa. The planar and absolute configurations of compounds 1 and 2 were established by MS, NMR spectral data analysis and Marfey’s method. Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time. Antibacterial and anti-tumor activities of compound 1 were measured against 15 drug-sensitive/resistant strains and 12 tumor cell lines. Compound 1 exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with the minimum inhibitory concentration (MIC) values ranged from 16 to 64 μg/mL. Moreover, it displayed remarkable anti-tumor activities; the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 μM.

Concepts: Cell, Cancer, Bacteria, Antibiotic resistance, NMR spectroscopy, Cell culture, Enterococcus, Enterococcus faecium

27

In addition to the primary α-process, some neat glass formers show a well resolved secondary β-process (type-B) or solely an excess wing (type-A). We investigate two binary glass forming systems composed of a type-A and a type-B component. (2)H nuclear magnetic resonance (NMR) spectroscopy is selectively applied to the type-B component in order to characterize the β-process over a large range of mole fractions x in the glassy state. We demonstrate that for x ≳ 0.75 the apparent relaxation strength is constant, i.e., all molecules of type-B participate in the β-process and the time constant τβ(T) is independent of concentration. For x < 0.75, however, the apparent relaxation strength decreases abruptly, which we interpret in terms of population: below this concentration a fraction ξ of type-B molecules still exhibits essentially the β-process of the neat system (in terms of time scale and mechanism), while others have been immobilized. The arise of such a scenario is verified by 2D and spin-lattice relaxation (2)H NMR techniques. In selective (2)H NMR experiments on the type-A component we observe a contribution to the β-process of the type-B molecules at medium concentrations. The latter finding and the rather sharp threshold occurring at x ≈ 0.75 may indicate that the β-process is a cooperative process.

Concepts: Spin, Nuclear magnetic resonance, NMR spectroscopy, Magnetic resonance imaging, Relaxation, Glass, Glass transition, Resonance

27

We derive a general formula for the paramagnetic NMR nuclear shielding tensor of an open-shell molecule in a pure spin state, subject to a zero-field splitting (ZFS). Our findings are in contradiction with a previous proposal. We present a simple application of the newly derived formula to the case of a triplet ground state split by an easy-plane ZFS spin Hamiltonian. When kT is much smaller than the ZFS gap, thus a single non-degenerate level is thermally populated, our approach correctly predicts a temperature-independent paramagnetic shift, while the previous theory leads to a Curie temperature dependence.

Concepts: Oxygen, Fundamental physics concepts, Nuclear magnetic resonance, NMR spectroscopy, Chemical shift, Paramagnetism

26

The potential ergogenic effects of oral salbutamol intake were demonstrated for decades but the underlying mechanisms remain to elucidate. We hypothesized that improved exercise performance after acute oral salbutamol administration is associated with changes in muscle metabolism. Twelve healthy, nonasthmatic, moderately trained, male subjects were recruited to compare in a double-blind crossover randomized study, an oral dose of salbutamol (4 mg) and a placebo. After treatment administration, subjects performed repetitive plantar flexions to exhaustion in a 3T magnet. Continuous (31) P nuclear magnetic resonance spectroscopy assessment of the calf muscles was performed at rest, during exercise, and during recovery. No significant difference between treatments was detected in metabolite concentration at rest (P > 0.05). Creatine phosphate and inorganic phosphate changes during and immediately after exercise were similar between treatments (P > 0.05). Intramuscular pH (pHi) was significantly higher at rest, at submaximal exercise but not at exhaustion with salbutamol (pHi at 50% of exercise duration, 6.8 ± 0.1/6.9 ± 0.1 for placebo and salbutamol, respectively, P < 0.05). The maximal power (28 ± 7 W/23 ± 7 W; P = 0.001) and total work (1702 ± 442 J/1381 ± 432 J; P = 0.003) performed during plantar flexions were significantly increased with salbutamol. Salbutamol induced significant improvement in calf muscle endurance with similar metabolic responses during exercise, except slight differences in pHi. Other mechanisms than changes in muscle metabolism may be responsible for the ergogenic effect of salbutamol administration.

Concepts: Metabolism, Muscle, Nuclear magnetic resonance, NMR spectroscopy, Phosphate, Magnetic resonance imaging, Difference, In vivo magnetic resonance spectroscopy

26

Abstract New compounds based on the indole moiety were synthesized via the reaction of indole-3-carbinal 1 with different nucleophiles such as 6-aryl-[4-(2-methoxybenzyl)pyridazin-3-yl] hydrazones 2a-c, benzidine, 3,3'-dimethoxybenzidine 4a,b and 2,6-diaminopyridine 6 to afford hydrazine derivatives 3a-c and three different classes of bis-Schiff bases. The structures of the new compounds were elucidated on the basis of their FTIR, (1)H NMR, (13)C NMR spectral data, GC/MS and elemental analysis. The antimicrobial activity of the new compounds was evaluated using a broth dilution technique in terms of minimal inhibitory concentration (MIC) against four pathogenic bacteria and two pathogenic fungi strains. Compound 14b showed excellent activity against Escherichia coli and Klebsiella pneumoniae. Some of the prepared compounds were tested for anti-cancer activity against human cell lines HCT116 (colon), MCF7 (breast) and HELA (cervix). From the results of the in vitro assays, compounds 3a,b, and 18a,c presented promising anti-cancer activity.

Concepts: Bacteria, Microbiology, Pneumonia, Escherichia coli, NMR spectroscopy, Cell culture, Enterobacteriaceae, Enterobacteria

26

A new neo-clerodane diterpene, named ajugacumbin J (1), together with 13 known compounds (2-14) was isolated from Ajuga decumbens. The structure of ajugacumbin J (1) was elucidated by 1D and 2D NMR spectra and MS. Ajugacumbin J (1) and ajugacumbin D (5) exhibited inhibition of lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages with an IC50 value of 46.2 and 35.9 μM, respectively.

Concepts: Nuclear magnetic resonance, NMR spectroscopy, Nitric oxide, Nitric acid

24

From the assignment of the solid-state (13)C NMR signals in the C4 region, distinct types of crystalline cellulose, cellulose at crystalline surfaces, and disordered cellulose can be identified and quantified. For regenerated cellulose, complete (13)C assignments of the other carbon regions have not previously been attainable, due to signal overlap. In this study, two-dimensional (2D) NMR correlation methods were used to resolve and assign (13)C signals for all carbon atoms in regenerated cellulose. (13)C-enriched bacterial nanocellulose was biosynthesized, dissolved, and coagulated as highly crystalline cellulose II. Specifically, four distinct (13)C signals were observed corresponding to conformationally different anhydroglucose units: two signals assigned to crystalline moieties and two signals assigned to non-crystalline species. The C1, C4 and C6 regions for cellulose II were fully examined by global spectral deconvolution, which yielded qualitative trends of the relative populations of the different cellulose moieties, as a function of wetting and drying treatments.

Concepts: Crystal, Atom, Chemical bond, NMR spectroscopy, Proton NMR, Carbon, Cellulose, Carbon-13

24

The identification of a drug candidate and its structural determination is the most important step in the process of the drug discovery and for this, nuclear magnetic resonance (NMR) is one of the most selective analytical techniques. Area covered: The present review illustrates the various perspectives of absolute quantitative (1)H NMR spectroscopy in drug discovery and development. It deals with the fundamentals of quantitative NMR (qNMR), the physiochemical properties affecting qNMR, and the latest referencing techniques used for quantification. The precise application of qNMR during various stages of drug discovery and development, namely natural product research, drug quantitation in dosage forms, drug metabolism studies, impurity profiling and solubility measurements is elaborated. To achieve this, the authors explore the literature of NMR in drug discovery and development between 1963 and 2015. It also takes into account several other reviews on the subject. Expert opinion: qNMR experiments are used for drug discovery and development processes as it is a non-destructive, versatile and robust technique with high intra and interpersonal variability. However, there are several limitations also. qNMR of complex biological samples is incorporated with peak overlap and a low limit of quantification and this can be overcome by using hyphenated chromatographic techniques in addition to NMR.

Concepts: Spectroscopy, Pharmacology, Nuclear magnetic resonance, NMR spectroscopy, Carbon-13 NMR, Magnetic resonance imaging, Analytical chemistry, Natural product

24

Japanese persimmon (Diospyros kaki L.) is recognized as an outstanding source of biologically active compounds relating to many health benefits. In the present study, NMR spectroscopy provided a comprehensive metabolic overview of Japanese persimmon juice. Detailed signal assignments of Japanese persimmon juice were carried out using various 2D NMR techniques incorporated with broadband water suppression enhanced through T1 effects (BB-WET) or WET sequences, and 26 components, including minor components, were identified. In addition, most components were quantitatively evaluated by the integration of signals using conventional (1) H NMR and BB-WET NMR. This is the first detailed analysis combined with quantitative characterization of chemical components using NMR for Japanese persimmon. Copyright © 2015 John Wiley & Sons, Ltd.

Concepts: Scientific method, Nuclear magnetic resonance, NMR spectroscopy, Proton NMR, Chemical shift, Carbon-13 NMR, Chemical compound, Persimmon