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Nature Reviews. Drug Discovery Jul 2023Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural... (Review)
Review
Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.
Topics: Humans; Deuterium; Drug Discovery; Chemistry, Pharmaceutical
PubMed: 37277503
DOI: 10.1038/s41573-023-00703-8 -
Current Opinion in Chemical Biology Oct 2022Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as... (Review)
Review
Raman microscopy has been used to deduce information about the distributions of endogenous biomolecules without exogenous labeling. Several functional groups, such as alkynes (CC), nitriles (CN), and carbon-deuterium (C-D) bonds, have been employed in recent years as Raman tags to detect target molecules in cells. In this article, we review some recent advances in applications using deuterated fatty acids for lipid analysis, such as investigation of tumor-selective cytotoxicity of γ-linolenic acid (GLA), simultaneous two-color imaging of stearate and oleate using deuterated and protonated alkynes, Raman hyperspectral imaging, and analyses of the physical properties of lipids through spectral unmixing of the C-D vibrational frequencies. In addition, we review some advanced methods for observing intracellular metabolic activities, such as de novo lipogenesis from deuterium-labeled precursors.
Topics: Alkynes; Carbon; Deuterium; Fatty Acids; Nitriles; Oleic Acid; Spectrum Analysis, Raman; Stearates; gamma-Linolenic Acid
PubMed: 35792373
DOI: 10.1016/j.cbpa.2022.102181 -
The Journal of Membrane Biology Oct 2022Biomembrane order, dynamics, and other essential physicochemical parameters are controlled by cholesterol, a major component of mammalian cell membranes. Although... (Review)
Review
Biomembrane order, dynamics, and other essential physicochemical parameters are controlled by cholesterol, a major component of mammalian cell membranes. Although cholesterol is well known to exhibit a condensing effect on fluid lipid membranes, the extent of stiffening that occurs with different degrees of lipid acyl chain unsaturation remains an enigma. In this review, we show that cholesterol locally increases the bending rigidity of both unsaturated and saturated lipid membranes, suggesting there may be a length-scale dependence of the bending modulus. We review our published data that address the origin of the mechanical effects of cholesterol on unsaturated and polyunsaturated lipid membranes and their role in biomembrane functions. Through a combination of solid-state deuterium NMR spectroscopy and neutron spin-echo spectroscopy, we show that changes in molecular packing cause the universal effects of cholesterol on the membrane bending rigidity. Our findings have broad implications for the role of cholesterol in lipid-protein interactions as well as raft-like mixtures, drug delivery applications, and the effects of antimicrobial peptides on lipid membranes.
Topics: Animals; Lipid Bilayers; Deuterium; Cholesterol; Cell Membrane; Magnetic Resonance Spectroscopy; Phosphatidylcholines; Mammals
PubMed: 36219221
DOI: 10.1007/s00232-022-00263-9 -
Angewandte Chemie (International Ed. in... Feb 2018Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct... (Review)
Review
Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.
Topics: Deuterium; Enzymes; Isotope Labeling; Kinetics; Metabolomics; Pharmaceutical Preparations; Proteomics; Tritium
PubMed: 28815899
DOI: 10.1002/anie.201704146 -
Chemical Reviews Mar 2022Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of... (Review)
Review
Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017-2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.
Topics: Deuterium; Hydrogen; Isotope Labeling; Mass Spectrometry; Tritium
PubMed: 35179363
DOI: 10.1021/acs.chemrev.1c00795 -
International Journal of Molecular... Feb 2023Deuterium, a stable isotope of hydrogen, is a component of water and organic compounds. It is the second most abundant element in the human body after sodium. Although... (Review)
Review
Deuterium, a stable isotope of hydrogen, is a component of water and organic compounds. It is the second most abundant element in the human body after sodium. Although the concentration of deuterium in an organism is much lower than that of protium, a wide variety of morphological, biochemical, and physiological changes are known to occur in deuterium-treated cells, including changes in fundamental processes such as cell division or energy metabolism. The mode and degree of changes in cells and tissues, both with an increase and a decrease in the concentration of deuterium, depends primarily on the time of exposure, as well as on the concentration. The reviewed data show that plant and animal cells are sensitive to deuterium content. Any shifts in the D/H balance outside or inside cells promote immediate responses. The review summarizes reported data on the proliferation and apoptosis of normal and neoplastic cells in different modes of deuteration and deuterium depletion in vivo and in vitro. The authors propose their own concept of the effects of changes in deuterium content in the body on cell proliferation and death. The altered rate of proliferation and apoptosis indicate a pivotal role of the hydrogen isotope content in living organisms and suggest the presence of a D/H sensor, which is yet to be detected.
Topics: Animals; Humans; Hydrogen; Deuterium; Water; Cell Division; Cell Cycle; Apoptosis
PubMed: 36834518
DOI: 10.3390/ijms24043107 -
Angewandte Chemie (International Ed. in... Jul 2022There is a constant need for deuterium-labelled products for multiple applications in life sciences and beyond. Here, a new class of heterogeneous catalysts is reported...
There is a constant need for deuterium-labelled products for multiple applications in life sciences and beyond. Here, a new class of heterogeneous catalysts is reported for practical deuterium incorporation in anilines, phenols, and heterocyclic substrates. The optimal material can be conveniently synthesised and allows for high deuterium incorporation using deuterium oxide as isotope source. This new catalyst has been fully characterised and successfully applied to the labelling of natural products as well as marketed drugs.
Topics: Aniline Compounds; Catalysis; Deuterium; Electrons; Manganese
PubMed: 35484978
DOI: 10.1002/anie.202202423 -
NMR in Biomedicine Sep 2021
Topics: Animals; Cell Line, Tumor; Deuterium; Humans; Magnetic Resonance Imaging; Mice; Pancreatic Neoplasms
PubMed: 34369021
DOI: 10.1002/nbm.4603 -
Progress in Nuclear Magnetic Resonance... 2023Deuterium metabolic imaging (DMI) is an emerging clinically-applicable technique for the non-invasive investigation of tissue metabolism. The generally short T values of... (Review)
Review
Deuterium metabolic imaging (DMI) is an emerging clinically-applicable technique for the non-invasive investigation of tissue metabolism. The generally short T values of H-labeled metabolites in vivo can compensate for the relatively low sensitivity of detection by allowing rapid signal acquisition in the absence of significant signal saturation. Studies with deuterated substrates, including [6,6'-H]glucose, [H]acetate, [H]choline and [2,3-H]fumarate have demonstrated the considerable potential of DMI for imaging tissue metabolism and cell death in vivo. The technique is evaluated here in comparison with established metabolic imaging techniques, including PET measurements of 2-deoxy-2-[F]fluoro-d-glucose (FDG) uptake and C MR imaging of the metabolism of hyperpolarized C-labeled substrates.
Topics: Deuterium; Magnetic Resonance Imaging; Cell Death
PubMed: 37321757
DOI: 10.1016/j.pnmrs.2023.02.002 -
The Journal of Nutrition Sep 2022Deuterium oxide (D2O) dilution is the criterion method for total body water (TBW) measurement, but results may vary depending on the specimen type, analysis method, and...
BACKGROUND
Deuterium oxide (D2O) dilution is the criterion method for total body water (TBW) measurement, but results may vary depending on the specimen type, analysis method, and analyzing laboratory. Bioelectrical impedance (BIA) estimates TBW, but results may vary by device make and model.
OBJECTIVES
We investigated the accuracy and precision of TBW estimates and how measurement conditions affected the accuracy of body composition using multicompartment body composition models.
METHODS
Eighty collegiate athletes received duplicate TBW measures acquired from 3 BIA devices (S10, SFB7, and SOZO) and from unique D2O combinations of specimen type (saliva, urine), analysis methodology [Fourier transform infrared spectrophotometry (FTIR), isotope-ratio mass spectrometry (IRMS)], and 3 different laboratories. TBW measures were substituted into 2-compartment (2C) and 5-compartment (5C) body composition models. Criterion measures were compared using Lin's concordance correlation coefficient cutoff of poor (<0.90), moderate (0.90-0.95), substantial (0.95-0.99), and almost perfect (>0.99).
RESULTS
Fifty-one participants (26 female) completed the protocol. Using IRMS saliva as the criterion TBW, all other measures produced a substantial or almost perfect agreement, except for SFB7 (poor) and SOZO (moderate). The 2C body composition measures using D2O and BIA produced poor agreement except for moderate agreement for lab 3 FTIR saliva. The 5C body composition measures using D2O produced a substantial agreement, whereas the BIA device S10 and SOZO had a moderate agreement, while the SFB7 had a poor agreement to the criterion. Test-retest precision varied between techniques from 0.3% to 1.2% for TBW.
CONCLUSIONS
Small differences in TBW measurement led to significant differences in 2C models. The 5C models partially mitigate differences seen in 2C models when different TBW measures are used. Interchanging TBW measures in multicompartment models can be problematic and should be performed with these considerations.
Topics: Athletes; Body Composition; Body Water; Deuterium; Deuterium Oxide; Electric Impedance; Female; Humans; Indicator Dilution Techniques
PubMed: 35665820
DOI: 10.1093/jn/nxac116