Solid-state NMR spectroscopic methods in chemistry

Over the last decades, NMR spectroscopy has grown into an indispensable tool for chemical analysis, structure determination, and the study of dynamics in organic, inorganic, and biological systems. It is commonly used for a wide range of applications from the characterization of synthetic products to the study of molecular structures of systems such as catalysts, polymers, and proteins. Although most NMR experiments are performed on liquid-state samples, solid-state NMR is rapidly emerging as a powerful method for the study of solid samples and materials. This Review outlines some of the developments of solid-state NMR spectroscopy, including techniques such as cross-polarization, magic-angle spinning, multiple-pulse sequences, homo- and heteronuclear decoupling and recoupling techniques, multiple-quantum spectroscopy, and dynamic angle spinning, as well as their applications to structure determination. Modern solid-state NMR spectroscopic techniques not only produce spectra with a resolution close to that of liquid-state spectra, but also capitalize on anisotropic interactions, which are often unavailable for liquid samples. With this background, the future of solid-state NMR spectroscopy in chemistry appears to be promising, indeed.     

From single to multiple microcoil flow probe NMR and related capillary techniques: a review

Nuclear magnetic resonance (NMR) spectroscopy is one of the most important and powerful instrumental analytical techniques for structural elucidation of unknown small and large (complex) isolated and synthesized compounds in organic and inorganic chemistry. X-ray crystallography, neutron scattering (neutron diffraction), and NMR spectroscopy are the only suitable methods for three-dimensional structure determination at atomic resolution. Moreover, these methods are complementary. However, by means of NMR spectroscopy, reaction dynamics and interaction processes can also be investigated. Unfortunately, this technique is very insensitive in comparison with other spectrometric (e.g., mass spectrometry) and spectroscopic (e.g., infrared spectroscopy) methods. Mainly through the development of stronger magnets and more sensitive solenoidal microcoil flow probes, this drawback has been successfully counteracted. Capillary NMR spectroscopy increases the mass-based sensitivity of the NMR spectroscopic analysis up to 100-fold compared with conventional 5-mm NMR probes, and thus can be coupled online and off-line with other microseparation and detection techniques. It offers not only higher sensitivity, but in many cases provides better quality spectra than traditional methods. Owing to the immense number of compounds (e.g., of natural product extracts and compound libraries) to be examined, single microcoil flow probe NMR spectroscopy will soon be far from being sufficiently effective as a screening method. For this reason, an inevitable trend towards coupled microseparation–multiple microcoil flow probe NMR techniques, which allow simultaneous online and off-line detection of several compounds, will occur. In this review we describe the current status and possible future developments of single and multiple microcoil capillary flow probe NMR spectroscopy and its application as a high-throughput tool for the analysis of a large number of mass-limited samples. The advantages and drawbacks of different coupled microseparation–capillary NMR spectroscopy techniques, such as capillary high-performance liquid chromatography–NMR spectroscopy, capillary electrophoresis–NMR spectroscopy, and capillary gas chromatography–NMR spectroscopy, are discussed and demonstrated by specific applications. Another subject of discussion is the progress in parallel NMR detection techniques. Furthermore, the applicability and mixing capability of tiny reactor systems, termed “microreactors” or “micromixers,” implemented in NMR probes is demonstrated by carbamate- and imine-forming reactions.     

NMR-based analysis of protein–ligand interactions

Physiological processes are mainly controlled by intermolecular recognition mechanisms involving protein–protein and protein–ligand (low molecular weight molecules) interactions. One of the most important tools for probing these interactions is high-field solution nuclear magnetic resonance (NMR) through protein-observed and ligand-observed experiments, where the protein receptor or the organic compounds are selectively detected. NMR binding experiments rely on comparison of NMR parameters of the free and bound states of the molecules. Ligand-observed methods are not limited by the protein molecular size and therefore have great applicability for analysing protein–ligand interactions. The use of these NMR techniques has considerably expanded in recent years, both in chemical biology and in drug discovery. We review here three major ligand-observed NMR methods that depend on the nuclear Overhauser effect—transferred nuclear Overhauser effect spectroscopy, saturation transfer difference spectroscopy and water–ligand interactions observed via gradient spectroscopy experiments—with the aim of reporting recent developments and applications for the characterization of protein–ligand complexes, including affinity measurements and structural determination.     

Application of multivariate data-analysis techniques to biomedical diagnostics based on mid-infrared spectroscopy

The objective of this contribution is to review the application of advanced multivariate data-analysis techniques in the field of mid-infrared (MIR) spectroscopic biomedical diagnosis. MIR spectroscopy is a powerful chemical analysis tool for detecting biomedically relevant constituents such as DNA/RNA, proteins, carbohydrates, lipids, etc., and even diseases or disease progression that may induce changes in the chemical composition or structure of biological systems including cells, tissues, and bio-fluids. However, MIR spectra of multiple constituents are usually characterized by strongly overlapping spectral features reflecting the complexity of biological samples. Consequently, MIR spectra of biological samples are frequently difficult to interpret by simple data-analysis techniques. Hence, with increasing complexity of the sample matrix more sophisticated mathematical and statistical data analysis routines are required for deconvoluting spectroscopic data and for providing useful results from information-rich spectroscopic signals. A large body of work relates to the combination of multivariate data-analysis techniques with MIR spectroscopy, and has been applied by a variety of research groups to biomedically relevant areas such as cancer detection and analysis, artery diseases, biomarkers, and other pathologies. The reported results indeed reveal a promising perspective for more widespread application of multivariate data analysis in assisting MIR spectroscopy as a screening or diagnostic tool in biomedical research and clinical studies. While the authors do not mean to ignore any relevant contributions to biomedical analysis across the entire electromagnetic spectrum, they confine the discussion in this contribution to the mid-infrared spectral range as a potentially very useful, yet underutilized frequency region. Selected representative examples without claiming completeness will demonstrate a range of biomedical diagnostic applications with particular emphasis on the advantageous interaction between multivariate data analysis and MIR spectroscopy.     

Advancement in the Biomedical Applications of the (Nano)gel Structures Based on Particular Polysaccharides

(Nano)gels from macromolecular compounds—natural, synthetic, or a combination thereof, suitable crosslinkers—and conferred characteristics—such as degradability, size, charge, amphiphilicity, responsiveness, and softness—are capable of responding to the challenges imposed by bioengineering applications. Polysaccharide‐based gels have received particular attention in this field. This review addresses recent advancement in the use of (nano)gel structures prepared only from compounds based on gellan gum, heparin, chondroitin sulfate, carrageenan, guar gum, galactose, or agarose, which represent an important part of the special class of natural polymers, the polysaccharides. Also, future trends are taken into discussion regarding the (nano)gels' use in biomedical applications such as biomimetics, biosensors, artificial muscles, and chemical separations in relation with their ability to be used as a vehicle for various biomolecules due to their physicochemical properties, biocompatibility, and biodegradability.     

NMR in natural products: understanding conformation, configuration and receptor interactions

Covering: up to 2011. Natural products are of tremendous importance in both traditional and modern medicine. For medicinal chemistry natural products represent a challenge, as their chemical synthesis and modification are complex processes, which require many, often stereo-selective, synthetic steps. A prerequisite for the design of analogs of natural products, with more accessible synthetic routes, is the availability of their bioactive conformation. Nuclear Magnetic Resonance (NMR) spectroscopy and X-ray crystallography are the two techniques of choice to investigate the structure of natural products. In this review, I describe the most recent advances in NMR to study the conformation of natural products either free in solution or bound to their cellular receptors. In chapter 2, I focus on the use of residual dipolar couplings (RDC). On the basis of a few examples, I discuss the benefit of complementing classical NMR parameters, such as NOEs and scalar couplings, with dipolar couplings to simultaneously determine both the conformation and the relative configuration of natural products in solution. Chapter 3 is dedicated to the study of the structure of natural products in complex with their cellular receptors and is further divided in two sections. In the first section, I describe two solution-state NMR methodologies to investigate the binding mode of low-affinity ligands to macromolecular receptors. The first approach, INPHARMA (Interligand Noes for PHArmacophore Mapping), is based on the observation of interligand NOEs between two small molecules binding competitively to a common receptor. INPHARMA reveals the relative binding mode of the two ligands, thus allowing ligand superimposition. The second approach is based on paramagnetic relaxation enhancement (PRE) of ligand resonances in the presence of a receptor containing a paramagnetic center. In the second section, I focus on solid-state NMR spectroscopy as a tool to access the bioactive conformation of natural products in complex with macromolecular receptors.     

Spectroscopic evidences of EDTA interaction with inorganic supports during the preparation of supported metal catalysts

Chelating compounds (etylenediaminetetraacetic acid (EDTA)-type reagents) are broadly applied in many chemical processes. One of the possible applications is their use in the preparation of the catalysts. A short summary based on my own experience in the spectroscopic studies on chelating molecules interaction with the surface of inorganic oxides is presented. The application of spectroscopic techniques allow to describe the nature and type of interactions. Particularly, the experiments conducted by an infrared spectroscopy method deliver valuable information which is of great importance for the adsorption and catalytic investigations.     

表面活性剂在水溶液中性质的质子核磁共振研究

综述了质子核磁共振的几种方法在表面活性剂水溶液研究中的应用.自从上世纪六十年代以来的许多研究表明核磁共振的各种技术是研究表面活性剂溶液的有效手段.它可以提供表面活性剂在水溶液中的cmc、胶束的结构、尺寸、水化、加溶性质和位置，不同表面活性剂胶束之间的相互作用，以及胶束与生物分子和高聚物的相互作用.化学位移已经成为惯常方法，弛豫测量提供动态信息，自扩散系数测量是研究胶束尺寸的很好手段.近来由于核磁共振技术的不断发展，用于研究生物大分子的2D NOESY和HOESY也逐渐应用到研究表面活性剂聚集结构中.由此可以得到有关表面活性剂在水溶液中行为的分子水平信息，是其它谱学方法所不能及的.     

糖-蛋白质相互作用

糖生物学被认为是生物化学领域“最后的前沿”。糖-蛋白质相互作用是信号传导、细胞粘附、病菌感染、受精、增殖、分化和免疫应答等很多细胞识别过程的基础,在生命科学中意义重大。本文综述了糖-蛋白质(尤其是凝集素)相互作用研究的电化学、压电传感、光谱学、纳米技术、微阵列技术和生物传感器等方法和器件及生物医学应用进展。     

Cyclic polymers: Advances in their synthesis,properties, and biomedical applications

Since the time first synthetic macrocycles were observed as academic curiosities, great advances have been made. Thanks to the development of controlled polymerization processes, new catalytic systems and characterization techniques during the last decades, well-defined cyclic polymers are now readily accessible. This further permits the determination of their unique set of properties, mainly due to their lack of chain ends, and their use for industrial applications can now be foreshadowed. This review aims to give an overview on the recent progresses in the field of ring polymers to this day. The current state of the art of the preparation of cyclic polymers, the challenges related to it such as the purification of the samples and the scalability of the synthetic processes, the properties arising from the cyclic topology and the potential use of cyclo-based polymers for biomedical applications are as many topics covered in this review.     

Emulsion Techniques for the Production of Pharmacological Nanoparticles

Nanoparticles have the advantages over micron‐sized particles to typically provide higher intracellular uptake and drug bioavailability. Emulsion techniques are commonly used methods for producing nanoparticles aiming at high encapsulation efficiency, high stability, and low toxicity. Here, the recent developments of nanoparticles prepared from emulsions, the synthesis of nanoparticles, their physicochemical properties, and their biomedical applications are discussed. Selection of techniques, such as emulsion polymerization, miniemulsion polymerization, microemulsion polymerization, and emulsion‐solvent evaporation processes, strongly influences morphologies, size distributions, and particle properties. Details in the synthetic strategies governing the performance of nanoparticles in bioimaging, biosensing, and drug delivery are presented. Benefits and limitations of molecular imaging techniques are also discussed.     

Synthetic peptide arrays and peptide combinatorial libraries for the exploration of protein-ligand interactions and the design of protein inhibitors

Synthetic peptides have a long tradition as molecular tools in biomedical research and drug discovery. The introduction of high-throughput synthesis and screening technologies for synthetic peptides, such as arrays and combinatorial libraries, enabled the large-scale and detailed exploration of protein-ligand interactions, as well as the discovery of novel biologically active peptides. This review summarizes currently available synthetic peptide array and library technologies, in particular mixture-based peptide libraries, which are illustrated by numerous applications in various fields of biomedical research.     

A fluorescence toolbox: A review of investigation of electrophoretic separations,process, and interfaces

This review focuses on fluorescence spectroscopy techniques for the investigation of electrophoretic separations. Fluorescence has been used as a sensitive detector for capillary, gel, and microchip electrophoresis for decades. However, advanced fluorescence methods can be used to study transport, interfacial phenomena, intermolecular and affinity interactions, and other processes that occur during separation. This so‐called spectroscopic toolkit can be implemented to understand fundamental behavior in electrophoresis and electrokinetic chromatography. Techniques such as fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and fluorescence anisotropy are discussed in relation to electrophoretic separations. Newer methods such as super‐resolution microscope are also introduced.     

On the Rational Drug Design for Hypertension through NMR Spectroscopy

Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state ¹³CP/MAS, ³¹P and ²H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.     

Synthesis and characterization of a new asymmetric bis-porphyrinato lanthanide complex presenting mixed hydrophilic-hydrophobic properties and its precursor form

The synthesis and spectroscopic characterization of a new family of heteroleptic porphyrinate double-deckers are reported. The investigated compounds are represented by the formulae La(III)H(TPyP)(TPP) and [La(III)(TMePyP)(TPP)]I(3). UV-vis spectroscopy of the title complexes confirms the presence of a strong pi-pi interaction between the macrocycles in each derivative. With (1)H and 2-D NMR data, we were able to distinguish two major NMR regions: the endo, between the bonded macrocycles, and the exo, outside the macrocycles, which are characteristic features of porphyrinic double-deckers. Finally, the electrochemical study confirms the strong pi-pi interaction for La(III)H(TPyP)(TPP) and completes this first approach for the investigation of this new family of derivatives.     

Synthesis of glycerol-thiophene nanoparticles,a suitable sensing platform for voltammetric determination of guaifenesin

Boronic acid functionalized materials have gained much attention in both chemistry and biology fields due to their multivalent covalent interactions with cis-diol containing (macro) molecules. The remarkable progress in this field has resulted in the development of their biomedical applications, such as, biosensors and nanocarriers. In this study, the spherical nanoparticles consisting of glycerol and 2,5-thiophenediylbisboronic acid were synthesized by one-pot ring opening copolymerization of a mixture of glycidol and 2,5-thiophenediylbisboronic acid. The synthesized nanoparticles were used for the modification of the glassy carbon electrode and the determination of Guaifenesin. The synthesized polymeric nanoparticles were characterized by different spectroscopic and microscopic methods including UV–vis, IR, NMR, DLS, and SEM. Additionally, the electrochemical behavior of the fabricated electrode toward Guaifenesin was investigated with cyclic voltammetry and electrochemical impedance spectroscopy.     

NOAH: NMR Supersequences for Small Molecule Analysis and Structure Elucidation

Nested NMR experiments combining up to five conventional NMR pulse sequences into one supersequence are introduced. The core 2D NMR techniques routinely employed in small molecule NMR spectroscopy, such as HSQC, HMQC, HMBC, COSY, NOESY, TOCSY, and similar, can be recorded in a single measurement. In this way the data collection time may be dramatically reduced and sample throughput increased for basic NMR applications, such as structure elucidation and verification in synthetic, medicinal, and natural product chemistry.     

Quantitative on-line high-resolution NMR spectroscopy in process engineering applications

In many technical processes, complex multicomponent mixtures have to be handled, for example, in reaction or separation equipment. High-resolution NMR spectroscopy is an excellent tool to study these mixtures and gain insight in their behavior in the processes. For on-line studies under process conditions, flow NMR probes can be used in a wide range of temperature and pressure. A major challenge in engineering applications of NMR spectroscopy is the need for quantitative evaluation. Flow rates, recovery times, and other parameters of the on-line NMR experiments have to be optimized for this purpose. Since it is generally prohibitive to use deuterated solvents in engineering applications, suitable techniques for field homogenization and solvent signal suppression are needed. Two examples for the application of on-line NMR spectroscopic experiments in process engineering are presented, studies on chemical equilibria and reaction kinetics of the technically important system formaldehyde-water-methanol and investigations on reactive gas absorption of CO(2) in aqueous solutions of monoethanolamine.     

Bisporphyrins with bischlorin features obtained by direct anodic coupling of porphyrins

The proximity of two or more porphyrin or chlorin-like structures has been shown to be crucial in numerous biological processes, such as electron transfers. The one-pot electrochemical synthesis of a dimeric tetraphenylporphyrin with one 1,2-(diphenylphosphonium)benzene as a spacer and of its porphyrin-monomer precursor are reported. These new compounds have been characterized by (1)H and (31)P NMR, ESR, and UV-visible spectroscopy and microanalysis. Electrochemical data are reported, and the redox behavior is analyzed for the monomers and the dimers. Important interactions between the two chromophores and a phosphonium-phosphonium interaction have been observed. UV-visible and (1)H NMR data along with electrochemical behavior suggest that the positive charge carried by the two phosphonium units is in part delocalized onto the pi system of the porphyrins, this gives an unexpected bis-porphyrin with bischlorin spectroscopic features.