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•Q ⊂ TSCX4 complex was characterized UV fluorescence, 2D NMR, HRMS experiments combined with density functional theory.•Quinoline is held within TSCX4 cavity by CH–--π, π---π and ...hydrogen bonding interactions as inferred from theory.•1H NMR titration and HRMS experiments ascertain 1:1 stoichiometry for the Q ⊂ TSCX4 complex.•band near 411 nm in fluorescence spectra in water display a blue-shift and significant intensity enhancement.•Bensai-Heildered method yields the binding constant 7.1 x 103 M−1 for the Q ⊂ TSCX4 complex in aqueous phase.
The inclusion complex between bowl-shaped para-sulfonatothiacalix4arene (TSCX4) macrocycle and quinoline has been studied with a unison of UV–visible, infra-red, flourescence emission and 1H nuclear magnetic resonance (NMR) and 2D nuclear overhauser effect spectroscopy (NOESY), high resolution mass spectrometry (HRMS) experiments. Both 1H NMR titration and HRMS experiments point to 1:1 stoichiometry for the water soluble Q⊂TSCX4 complex. The electronic structure of the inclusion complex obtained from density functional theory (DFT) showed a partial encapsulation of quinoline guest, which is held within the host cavity by C–H---π, π---π and hydrogen bonding interactions. The fluorescence emission spectra upon complexation display marginal blue shift of the 411 nm band in TSCX4. Moreover, the binding constant (7.1 × 103 M−1) determined from fluoresence emission experiments underline the effective host–guest binding in the complex, which was corroborated through frequency up-shift (‘blue shift’) of characteristic Ar-OH (3433 cm−1) and SO3- vibrations (1141 cm−1 and 1037 cm−1) in the measured infrared spectra of TSCX4. The antiproliferative activitities of the Q⊂TSCX4 complex against HeLA, MDA-MB-231and N2a cells are presented. The Q⊂TSCX4 complex has been shown to be efficient against N2a (neuroblastoma) cell line.
In‐cell NMR spectroscopy has emerged as a powerful technique for monitoring biomolecular interactions at an atomic level inside intact cells. However, current methodologies are inadequate at charting ...intracellular interactions of nonlabeled proteins and require their prior isotopic labeling. Herein, we describe for the first time the monitoring of the quercetin‐alanine bioconjugate interaction with the nonlabeled antiapoptotic protein Bcl‐2 inside living human cancer cells. STD and Tr‐NOESY in‐cell NMR methodologies were successfully applied in the investigation of the binding, which was further validated in vitro. In‐cell NMR proved a very promising strategy for the real‐time probing of the interaction profile of potential drugs with their therapeutic targets in native cellular environments and could, thus, open a new avenue in drug discovery.
The interactions between ionic liquids and water are very important for the chemical industry. The advancement of research between levels of interactions and the presence of clustering can boost the ...pharmaceutical industry and of polymers. The aim of this work was to use different protic ionic liquids to observe the formation of aggregated using the NMR 1D NOESY. The results reveal the presence of Nuclear Overhauser Effect in some systems and the behavior of the NOE effect does not seem to be so linear, that is, the increase in the size of the alkyl chain lengths ranging does not guarantee the presence of supra molecular aggregates.
•Nuclear Overhauser effect has been investigated in ionic liquids.•Nuclear Overhauser and NOE effects have been compared in liquid system.•Presence of supra molecular aggregates has been investigated.
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•Curcumin adopts a carpet disposition in the membrane.•The curcumin moiety of bivalent compounds is found in a more polar environment than pure curcumin.•Curcumin and bivalent ...compounds show a poor miscibility with phospholipids.
Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself. 1H NOESY MAS-NMR analysis supports this notion by showing that the orientation of curcumin was parallel to the plane of the membrane surface close to C2 and C3 of the fatty acyl chains, while the curcumin moiety of 17MD and 21MO positioned close to the polar part of the membrane with the steroid moiety in the centre of the membrane. Molecular dynamics studies were in close agreement with the experimental results with respect to the likely proximity of the protons studied by NMR and show that 17MD and 21MO have a clear tendency to aggregate in a fluid membrane. The anchorage of the bivalent compounds to the membrane leaving the curcumin moiety near the polar part may be very important to facilitate the bioactivity of the curcumin moiety when used as anti-Alzheimer drugs.
The potencies of aza-nitriles toward cathepsin K have been well explained using the molecular docking program GOLD 5.1. However, this is insufficient to explain the selectivity of these inhibitors ...for cathepsin K over cathepsins L, S and B. In this study, the optimal binding models of aza-nitriles in cathepsins were constructed through structure optimization and reasonable dislodging of unfavorable binding configurations. The spatial structures of aza-nitriles were analyzed through 1H–1H COSY and 1H–1H NOESY, as well as through basic analysis of 1H NMR, 13C NMR and HPLC-MS (ESI) as reported in previous studies. All docking results were subsequently screened and any warped and/or seriously incompatible models were removed by scoring (high to low) until the most suitable docking mode with proper configuration and a high score was found, which was used for further analysis. The final results exhibited Goldscore fitness ratios that correlate well with the known selectivities of aza-nitriles for cathepsin K over cathepsins L, S. Such improvements would be useful to predict more selective inhibitors in drug development.
•The spatial structural of aza-nitriles were analyzed through 1H–1H COSY and 1H–1H NOESY.•All the docking results were screened to find the most suitable docking mode with proper configuration and high score.•The optimized Goldscore fitness ratios were correlated well with the selectivity of aza-nitriles toward cathepsin K.
HMBC‐ und NOESY‐NMR‐Spektroskopie Findeisen, Matthias; Siehl, Hans Ullrich; Berger, Stefan
Chemie in unserer Zeit,
December 2017, Volume:
51, Issue:
6
Journal Article
Peer reviewed
Zusammenfassung
In diesem Artikel diskutieren wir zunächst die NMR‐Pulssequenz HMBC (heteronuclear multiple bond correlation) und zeigen ihre Mächtigkeit bei der endgültigen Strukturabsicherung des ...Naturstoffs Cytisin, dessen 1H‐, 13C‐, COSY‐ und HSQC‐Spektren wir in den ersten beiden Artikeln dieser Serie vorgestellt haben. Danach wird die Physik des NOESY‐Experiments (nuclear Overhauser effect spectroscopy) erläutert und zur Klärung stereochemischer Zuordnung der Protonensignale verwendet. Ein Korrelationsdiagramm zwischen den NOE‐Integralen und den Kernspinabständen bestätigt die korrekte Analyse der vorgestellten Spektren.
Summary
In this article we first discuss the NMR pulse sequence HMBC (heteronuclear multiple bond correlation) and demonstrate its importance for the final structure verification of the natural product cytisine. The 1H‐, 13C‐, COSY‐ und HSQC‐spectra of this compound have been shown in the first two articles of this series. After this we explain the physics of the NOESY‐experiment (nuclear Overhauser effect spectroscopy) and apply this for the stereochemical assignment of the proton signals. A correlation diagram between NOE integrals and hydrogen atom distances proofs the correct analysis.
Im ersten Artikel dieser Serie 1 haben wir gezeigt, wie man mit den 1H‐ und 13C‐NMR‐Spektren eines Naturstoffs zu vernünftigen Strukturfragmenten gelangt und eine wahrscheinliche Summenformel entwickeln kann. Im zweiten Artikel 2 konnten wir dann mittels 2D COSY‐ und 2D HSQC‐NMR diese Strukturelemente zu einem überzeugenden Strukturvorschlag zusammenfassen. In diesem abschließenden Bericht folgt die endgültige Absicherung mittels der 2D HMBC‐ sowie die Klärung stereochemischer Details durch 2D NOESY‐NMR‐Spektroskopie. Damit wird gezeigt, dass der „organische Satz“ 3 (1H‐, APT‐13C‐, COSY‐ HSQC‐ HMBC‐ und NOESY‐NMR‐Spektren) im Allgemeinen für eine Strukturaufklärung im Molekulargewichtsbereich bis 1000 Da ausreicht.
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3-(1-Aryl-2-nitrovinyl)-indoles were previously described in the literature only once as side products of an unrelated process as mixtures of Z- and E-isomers. Herein, we discovered a ...new process toward their synthesis where substituted indoles are combined with 2-nitroacetophenones in acetic acid in the presence of 10 mol% H2SO4 to give 70–90% yields of such compounds possessing exclusively or predominantly Z-geometry. The latter was established through NOESY and x-ray studies of individual products.
Non-steroidal anti-inflammatory drugs (NSAIDs) have antipyretic, anti-inflammatory and analgesic effects, and can be used in the treatment of various diseases. These drugs have also a number of side ...effects, which may be related to their interaction with lipid membranes. In this study, we use the spin-labeled NSAID ibuprofen (ibuprofen-SL) as a relaxation enhancer to study its interaction with model lipid membranes employing liquid-state 1H NMR at 500 MHz. The high magnetic moment of unpaired electron in the spin label made it possible to reduce the concentration of the studied drug in the membrane to tenths of a mole percent. As model membranes, unilamellar POPC liposomes and bicelles consisting of a 2:1 mixture of DHPC:DMPC or DHPC:POPC lipids were used. An increase in the rate of proton spin-lattice relaxation, T1−1, selectively detected for protons at different positions in the lipid molecule, showed that ibuprofen-SL is localized in the hydrophobic part of the lipid bilayer. As the concentration of ibuprofen-SL increases to 0.5 mol%, the distribution of positions of ibuprofen-SL across the bilayer becomes wider. In the presence of 20 mol% of cholesterol, ibuprofen-SL is displaced from the core of the membrane to a region closer to the head group of the bilayer. This displacement was also confirmed by the NMR NOESY experiment conducted with unlabeled ibuprofen. For bilayers containing unsaturated POPC lipids, the distribution of ibuprofen positions across the bilayer becomes narrower compared to the presence of saturated DMPC lipids.
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•NMR relaxation assesses the position of the spin label across the membrane.•The approach is sensitive to spin-labeled molecules with a concentration of ~0.2 mol%.•Ibuprofen is embedded in a bilayer hydrophobic interior.•Cholesterol expels ibuprofen from the center of the bilayer.•Ibuprofen is attracted to kinks in the lipid structure.
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