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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 -
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 -
Journal of Magnetic Resonance (San... May 2021Deuterium metabolic spectroscopy (DMS) and imaging (DMI) have recently been described as simple and robust MR-based methods to map metabolism with high temporal and/or... (Review)
Review
Deuterium metabolic spectroscopy (DMS) and imaging (DMI) have recently been described as simple and robust MR-based methods to map metabolism with high temporal and/or spatial resolution. The metabolic fate of a wide range of suitable deuterated substrates, including glucose and acetate, can be monitored with deuterium MR methods in which the favorable MR characteristics of deuterium prevent many of the complications that hamper other techniques. The short T relaxation times lead to good MR sensitivity, while the low natural abundance prevents the need for water or lipid suppression. The sparsity of the deuterium spectra in combination with the low resonance frequency provides relative immunity to magnetic field inhomogeneity. Taken together, these features combine into a highly robust metabolic imaging method that has strong potential to become a dominant MR research tool and a viable clinical imaging modality. This perspective reviews the history of deuterium as a metabolic tracer, the use of NMR as a detection method for deuterium in vitro and in vivo and the recent development of DMS and DMI. Following a review of the NMR characteristics and the biological effects of deuterium, the promising future of DMI is outlined.
Topics: Acetates; Deuterium; Glucose; Magnetic Resonance Spectroscopy; Water
PubMed: 33902815
DOI: 10.1016/j.jmr.2021.106932 -
Nature Communications Jun 2024Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks,...
Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks, allowing for the incorporation of deuterium atoms and functional groups into a target molecule in a single step. Unfortunately, the limited availability of synthetic approaches to deuterated synthons has impeded progress in this field. Here, we present an approach utilizing alkyl-substituted thianthrenium salts that efficiently and selectively introduce deuterium at the α position of alkyl chains through a pH-dependent HIE process, using DO as the deuterium source. The resulting α-deuterated alkyl thianthrenium salts, which bear two deuterium atoms, exhibit excellent selectivity and deuterium incorporation in electrophilic substitution reactions. Through in situ formation of isotopically labelled alkyl halides, these thianthrenium salts demonstrate excellent compatibility in a series of metallaphotoredox cross-electrophile coupling with (hetero)aryl, alkenyl, alkyl bromides, and other alkyl thianthrenium salts. Our technique allows for a wide range of substrates, high deuterium incorporation, and precise control over the site of deuterium insertion within a molecule such as the benzyl position, allylic position, or any alkyl chain in between, as well as neighboring heteroatoms. This makes it invaluable for synthesizing various deuterium-labeled compounds, especially those with pharmaceutical significance.
PubMed: 38871683
DOI: 10.1038/s41467-024-48590-w -
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 -
Chemical Science Aug 2022The development of chemoselective C(sp)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective,...
The development of chemoselective C(sp)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen(H)/deuterium(D) isotope exchange of alcohols using deuterium oxide (DO) as the primary deuterium source. This method enables the direct, chemoselective deuteration of primary and secondary alcohols under basic or neutral conditions without being affected by coordinative functional groups such as imidazole and tetrazole. Successful substrates for deuterium labelling include the pharmaceuticals losartan potassium, rapidosept, guaifenesin, and diprophylline. The deuterated losartan potassium shows higher stability towards the metabolism by CYP2C9 than the protiated analogue. Kinetic and DFT studies indicate that the direct deuteration proceeds through dehydrogenation of alcohol to the carbonyl intermediate, conversion of [Ir-H] to [Ir-D] with DO, and deuteration of the carbonyl intermediate to give the α-deuterated product.
PubMed: 35975159
DOI: 10.1039/d2sc01805e -
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 -
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