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Chemical Society Reviews Apr 2022C-H deuteration has been intricately developed to satisfy the urgent need for site-selectively deuterated organic frameworks. Deuteration has been primarily used to... (Review)
Review
C-H deuteration has been intricately developed to satisfy the urgent need for site-selectively deuterated organic frameworks. Deuteration has been primarily used to study kinetic isotope effects of reactions but recently its significance in pharmaceutical chemistry has been discovered. Deuterium labelled compounds have stolen the limelight since the inception of the first FDA-approved deuterated drug, for the treatment of chorea-associated Huntington's disease, and their pharmacological importance was realised by chemists, although surprisingly very late. Various approaches were developed to carry out site-selective deuteration. However, the most common and efficient method is hydrogen isotope exchange (HIE). This review summarises deuteration methods of various organic motifs containing C(sp)-H and C(sp)-H bonds utilizing C-H bond functionalisation as a key step along with a variety of catalysts, and exemplifies their biological relevance.
Topics: Amines; Catalysis; Deuterium; Hydrogen; Kinetics
PubMed: 35320331
DOI: 10.1039/d0cs01496f -
Journal of Labelled Compounds &... Aug 2023The direct electrophilic deuteration of the aromatic moiety in aromatic and aralkyl amines is reported. The acid-catalyzed deuteration is facilitated by deuterated...
The direct electrophilic deuteration of the aromatic moiety in aromatic and aralkyl amines is reported. The acid-catalyzed deuteration is facilitated by deuterated trifluoromethanesulfonic acid, [D]triflic acid, CF SO D, TfOD, which acts as both the reaction solvent and the source of the deuterium label. The mild conditions enable room temperature hydrogen/deuterium exchange for most of the para-substituted aromatic amine derivatives studied. In addition, short reaction times and a high degree of aromatic deuteration are achieved and isolation of the product is simple. The optical activity of the chiral aralkyl amines studied was preserved.
Topics: Hydrogen; Deuterium; Amines; Deuterium Exchange Measurement
PubMed: 37337654
DOI: 10.1002/jlcr.4048 -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2022The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic...
The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium-modified drugs directly from their non-labeled parents. While most of the recent studies focus on metal-catalyzed C-H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late-stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures.
Topics: Deuterium; Hydrogen; Pharmaceutical Preparations
PubMed: 35689822
DOI: 10.1002/chem.202201583 -
The International Journal of... Dec 2017The growing prevalence of metabolic diseases including fatty liver disease and Type 2 diabetes has increased the emphasis on understanding metabolism at the mechanistic... (Review)
Review
The growing prevalence of metabolic diseases including fatty liver disease and Type 2 diabetes has increased the emphasis on understanding metabolism at the mechanistic level and how it is perturbed in disease. Metabolomics is a continually expanding field that seeks to measure metabolites in biological systems during a physiological stimulus or a genetic alteration. Typically, metabolomics studies provide total pool sizes of metabolites rather than dynamic flux measurements. More recently there has been a resurgence in approaches that use stable isotopes (e.g. H and C) for the unambiguous tracking of individual atoms through compartmentalised metabolic networks in humans to determine underlying mechanisms. This is known as metabolic flux analysis and enables the capture of a dynamic picture of the metabolome and its interactions with the genome and proteome. In this review, we describe current approaches using stable isotope labelling in the field of metabolomics and provide examples of studies that led to an improved understanding of glucose, fatty acid and amino acid metabolism in humans, particularly in relation to metabolic disease. Examples include the use of stable isotopes of glucose to study tumour bioenergetics as well as brain metabolism during traumatic brain injury. Lipid tracers have also been used to measure non-esterified fatty acid production whilst amino acid tracers have been used to study the rate of protein digestion on whole body postprandial protein metabolism. In addition, we illustrate the use of stable isotopes for measuring flux in human physiology by providing examples of breath tests to measure insulin resistance and gastric emptying rates.
Topics: Carbon Isotopes; Deuterium; Humans; Metabolic Diseases; Metabolome
PubMed: 28736244
DOI: 10.1016/j.biocel.2017.07.012 -
Analytica Chimica Acta Feb 2023Mass spectrometry (MS) is an invaluable tool for sensitive detection and characterization of individual biomolecules in omics studies. MS combined with stable isotope... (Review)
Review
Mass spectrometry (MS) is an invaluable tool for sensitive detection and characterization of individual biomolecules in omics studies. MS combined with stable isotope labeling enables the accurate and precise determination of quantitative changes occurring in biological samples. Metabolic isotope labeling, wherein isotopes are introduced into biomolecules through biosynthetic metabolism, is one of the main labeling strategies. Among the precursors employed in metabolic isotope labeling, deuterium oxide (DO) is cost-effective and easy to implement in any biological systems. This tutorial review aims to explain the basic principle of DO labeling and its applications in omics research. DO labeling incorporates D into stable C-H bonds in various biomolecules, including nucleotides, proteins, lipids, and carbohydrates. Typically, DO labeling is performed at low enrichment of 1%-10% DO, which causes subtle changes in the isotopic distribution of a biomolecule, instead of the complete separation between labeled and unlabeled samples in a mass spectrum. DO labeling has been employed in various omics studies to determine the metabolic flux, turnover rate, and relative quantification. Moreover, the advantages and challenges of DO labeling and its future prospects in quantitative omics are discussed. The economy, versatility, and convenience of DO labeling will be beneficial for the long-term omics studies for higher organisms.
Topics: Deuterium Oxide; Mass Spectrometry; Isotopes; Proteins; Isotope Labeling
PubMed: 36657897
DOI: 10.1016/j.aca.2022.340722 -
Journal of the American Society For... Apr 2022This note describes theoretical and experimental considerations to observe perturbation of a protein upon binding to a ligand with weak affinity by hydrogen/deuterium...
This note describes theoretical and experimental considerations to observe perturbation of a protein upon binding to a ligand with weak affinity by hydrogen/deuterium exchange mass spectrometry (HDX-MS). The most popular application of HDX-MS is to determine the binding site of a drug or drug lead in a protein target. However, when the affinity of a ligand is weak, driving the equilibrium to the formation of a complex is difficult, and thus, observing the perturbation upon binding is also challenging. Theoretical consideration indicates that the original concentration of a ligand over the dissociation constant ([L]/) is roughly equal to the maximum protection factor expected for the experiment when the original concentration of a ligand is significantly larger than the original concentration of a protein and the dissociation constant ([L] ≫ [P] and [L] ≫ ). When HDX-MS analysis of a protein with a ligand of low affinity and low solubility is carried out, it may be challenging to achieve high enough ligand concentration to drive the equilibrium in favor of the complex due to the low solubility. There are two methods to alleviate this issue: (i) spiking a low affinity/low solubility ligand to exchange buffer to lower the required ligand concentration in aqueous protein stock solution and (ii) mixing a 1:1 ratio of aqueous protein-ligand stock solution and deuterated buffer to initiate the exchange reaction instead of the commonly used 1:9 ratio.
Topics: Deuterium; Deuterium Exchange Measurement; Hydrogen Deuterium Exchange-Mass Spectrometry; Mass Spectrometry; Proteins
PubMed: 35230104
DOI: 10.1021/jasms.1c00375 -
Organic Letters Nov 2022Deuteration of arylthianthren-5-ium triflates with CDOD or CDOD/CDCOCD in the presence of CsCO by palladium catalysis or photoirradiation allowed the convenient...
Deuteration of arylthianthren-5-ium triflates with CDOD or CDOD/CDCOCD in the presence of CsCO by palladium catalysis or photoirradiation allowed the convenient synthesis of deuterated arenes in good yields. The Pd-catalyzed reaction generally gave better yields than the photoinduced deuteration, but exceptions also exist. They could complement each other in some cases. These reactions featured eco-friendly conditions, simplicity, inexpensive deuterium sources, good functional group tolerance, and a range of substrates. Since arylthianthren-5-ium salts could be readily synthesized from arenes and thianthrene 5-oxide, this protocol provided a formal aromatic C-H deuteration with high selectivity, enabling efficient deuterium labeling of multifunctionalized arenes and drug molecules.
Topics: Deuterium; Salts; Catalysis; Palladium
PubMed: 36342364
DOI: 10.1021/acs.orglett.2c03541 -
Pediatric Pulmonology Nov 2022Stable isotope tracers, like C, can be used for the measurement of the partition between the endogenous and exogenous pulmonary disaturated-phosphatidylcholine (DSPC)....
Stable isotope tracers, like C, can be used for the measurement of the partition between the endogenous and exogenous pulmonary disaturated-phosphatidylcholine (DSPC). Deuterium labeling methods are still not fully explored. Our aim was to investigate the feasibility of using deuterium-depleted water (DDW) and deuterium-enriched water (DEW) to measure endogenous and exogenous pulmonary DSPC in a rabbit model of surfactant depletion. Data obtained from the C dilution method were used as a reference. We studied 9 adult rabbits: 4 drank DDW and 5 DEW for 5 days. Lung surfactant depletion was induced at Day 5 by repeated saline bronchoalveolar lavages (BAL), which were stored as a pool (BAL pool). After endogenous surfactant depletion, rabbits received exogenous surfactant followed by a second BAL depletion procedure (End-Experiment Pool). DSPC quantity, and palmitic acid (PA)-DSPC H/ H (δ H) and C/ C ratios (δ C) of exogenous surfactant batches and of BAL pools were measured by High-Resolution Mass Spectrometry. The amount of exogenous surfactant recovered from the lungs ranged from 45% to 81% and, it was highly correlated with those obtained with the use of the C (r = 0.9844, p < 0.0001). We demonstrated that commercially available purified DDW and even low doses of DEW can be used to modify the deuterium background of endogenous surfactants with the purpose of measuring the contribution of exogenous surfactants to the endogenous alveolar surfactant pool.
Topics: Animals; Deuterium; Palmitic Acid; Phosphatidylcholines; Pulmonary Surfactants; Rabbits; Surface-Active Agents; Water
PubMed: 35938216
DOI: 10.1002/ppul.26104 -
Journal of Labelled Compounds &... Mar 2023Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological...
Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium's ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.
Topics: Deuterium; Cycloparaffins; Hydrogen; Copper; Catalysis; Alkenes
PubMed: 36772856
DOI: 10.1002/jlcr.4015 -
Analytical Chemistry Jun 2021Raman-stable isotope labeling using heavy water (Raman-DO) is attracting great interest as a fast technique with various applications ranging from the identification of...
Raman-stable isotope labeling using heavy water (Raman-DO) is attracting great interest as a fast technique with various applications ranging from the identification of pathogens in medical samples to the determination of microbial activity in the environment. Despite its widespread applications, little is known about the fundamental processes of hydrogen-deuterium (H/D) exchange, which are crucial for understanding molecular interactions in microorganisms. By combining two-dimensional (2D) correlation spectroscopy and Raman deuterium labeling, we have investigated H/D exchange in bacterial cells under time dependence. Most C-H stretching signals decreased in intensity over time, prior to the formation of the C-D stretching vibration signals. The intensity of the C-D signal gradually increased over time, and the shape of the C-D signal was more uniform after longer incubation times. Deuterium uptake showed high variability between the bacterial genera and mainly led to an observable labeling of methylene and methyl groups. Thus, the C-D signal encompassed a combination of symmetric and antisymmetric CD and CD stretching vibrations, depending on the bacterial genera. The present study allowed for the determination of the sequential order of deuterium incorporation into the functional groups of proteins, lipids, and nucleic acids and hence understanding the process of biomolecule synthesis and the growth strategies of different bacterial taxa. We present the combination of Raman-DO labeling and 2D correlation spectroscopy as a promising approach to gain a fundamental understanding of molecular interactions in biological systems.
Topics: Bacteria; Deuterium; Deuterium Oxide; Isotope Labeling; Spectrum Analysis, Raman
PubMed: 34014079
DOI: 10.1021/acs.analchem.1c01076