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Clinical Cancer Research : An Official... Dec 2023An accurate and noninvasive assessment of tumor response following treatment other than traditional anatomical imaging techniques is essential. Deuterium magnetic...
PURPOSE
An accurate and noninvasive assessment of tumor response following treatment other than traditional anatomical imaging techniques is essential. Deuterium magnetic resonance spectroscopic (MRS) imaging has been demonstrated as an alternative for cancer metabolic imaging by high-field MRI using deuterium-labeled molecules. The study aim was to use 2H tissue labeling and deuterium MRI at clinical field strength for tumor visualization and assessment of three anticancer therapies in pancreatic cancer model mice.
EXPERIMENTAL DESIGN
MIA PaCa-2 pancreatic carcinoma and C26 colorectal carcinoma models of BALB/c-nu mice was prepared, and repeated deuterium MRI was performed during the first 10 days of free drinking of 30% D2O to track 2H distribution in tissues. 2H accumulation in the tumor after irradiation, bevacizumab administration, or gemcitabine administration was also measured in MIA PaCa-2-bearing mice. Confirmatory proton MRI, ex vivo metabolic hyperpolarization 13C-MRS, and histopathology were performed.
RESULTS
The mouse's whole-body distribution of 2H was visible 1 day after drinking, and the signal intensity increased daily. Although the tumor size did not change 1 and 3 days after irradiation, the amount of 2H decreased significantly. The 2H image intensity of the tumor also significantly decreased after the administration of bevacizumab or gemcitabine. Metabolic hyperpolarization 13C-MRS, proton MRI, and 2H-NMR spectroscopy confirmed the efficacy of the anticancer treatments.
CONCLUSIONS
Deuterium MRI at 1.5T proved feasible to track 2H distribution throughout mouse tissues during D2O administration and revealed a higher 2H accumulation in the tumor xenografts. This research demonstrated a promising successful method for preliminary assessment of radiotherapy and chemotherapy of cancer.
Topics: Humans; Mice; Animals; Water; Deuterium; Protons; Bevacizumab; Gemcitabine; Magnetic Resonance Imaging; Neoplasms
PubMed: 37732903
DOI: 10.1158/1078-0432.CCR-23-1635 -
Angewandte Chemie (International Ed. in... Mar 2024We report herein the development of palladium-catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance,...
We report herein the development of palladium-catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance, heterocyclic compatibility, and high deuterium incorporation levels. Regioselective deuteration of some biologically important drugs and natural products are showcased via Friedel-Crafts acylation and subsequent deacylative deuteration. Vicinal meta-C-H bond functionalization (including fluorination, arylation, and alkylation) and para-C-H bond deuteration of electro-rich arenes are realized by using the ketone as both directing group and leaving group, which is distinct from aryl halide in conventional dehalogenative deuteration.
PubMed: 38279666
DOI: 10.1002/anie.202319773 -
Journal of Labelled Compounds &... May 2024Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has...
Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid.
Topics: Quinolones; Deuterium; Chemistry Techniques, Synthetic; Prodrugs; Antimalarials
PubMed: 38661253
DOI: 10.1002/jlcr.4092 -
Carbohydrate Research Aug 2023Carbohydrates and glycans are integral to many biological processes, including cell-cell recognition and energy storage. However, carbohydrates are often difficult to...
Carbohydrates and glycans are integral to many biological processes, including cell-cell recognition and energy storage. However, carbohydrates are often difficult to analyze due to the high degree of isomerism present. One method being developed to distinguish these isomeric species is hydrogen/deuterium exchange-mass spectrometry (HDX-MS). In HDX-MS, carbohydrates are exposed to a deuterated reagent and the functional groups with labile hydrogen atoms, including hydroxyls and amides, exchange with the 1 amu heavier isotope, deuterium. These labels can then be detected by MS, which monitors the mass increase with the addition of D-labels. The observed rate of exchange is dependent on the exchanging functional group, the accessibility of the exchanging functional group, and the presence of hydrogen bonds. Herein, we discuss how HDX has been applied in the solution-phase, gas-phase, and during MS ionization to label carbohydrates and glycans. Additionally, we compare differences in the conformations that are labeled, the labeling timeframes, and applications of each of these methods. Finally, we comment on future opportunities for development and use of HDX-MS to analyze glycans and glycoconjugates.
Topics: Hydrogen; Deuterium; Carbohydrates; Amides; Hexoses
PubMed: 37290371
DOI: 10.1016/j.carres.2023.108859 -
Translational Exercise Biomedicine May 2024'OMICs encapsulates study of scaled data acquisition, at the levels of DNA, RNA, protein, and metabolite species. The broad objectives of OMICs in biomedical exercise... (Review)
Review
OBJECTIVES
'OMICs encapsulates study of scaled data acquisition, at the levels of DNA, RNA, protein, and metabolite species. The broad objectives of OMICs in biomedical exercise research are multifarious, but commonly relate to biomarker development and understanding features of exercise adaptation in health, ageing and metabolic diseases.
METHODS
This field is one of exponential technical (i.e., depth of feature coverage) and scientific (i.e., in health, metabolic conditions and ageing, multi-OMICs) progress adopting and approaches.
RESULTS
Key findings in exercise biomedicine have led to the identification of OMIC features linking to heritability or adaptive responses to exercise e.g., the forging of GWAS/proteome/metabolome links to cardiovascular fitness and metabolic health adaptations. The recent addition of stable isotope tracing to proteomics ('dynamic proteomics') and metabolomics ('fluxomics') represents the next phase of state-of-the-art in 'OMICS.
CONCLUSIONS
These methods overcome limitations associated with point-in-time 'OMICs and can be achieved using substrate-specific tracers or deuterium oxide (DO), depending on the question; these methods could help identify how individual protein turnover and metabolite flux may explain exercise responses. We contend application of these methods will shed new light in translational exercise biomedicine.
PubMed: 38660119
DOI: 10.1515/teb-2024-2006 -
Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides.Molecular & Cellular Proteomics : MCP Aug 2023Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy...
Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson's Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide-containing compound, USP30. Activity-based protein profiling mass spectrometry confirmed target engagement, high selectivity, and potency of USP30 for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. In vitro characterization of USP30 enzyme kinetics inferred slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen-deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with USP30, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that USP30 binds to this thumb-palm cleft, which guides the ubiquitin C terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.
Topics: Deubiquitinating Enzymes; Mitochondrial Proteins; Mitophagy; Ubiquitin-Protein Ligases; Ubiquitination; Sulfonamides
PubMed: 37385347
DOI: 10.1016/j.mcpro.2023.100609 -
Frontiers in Oncology 2023Cancer metabolism has emerged as a pivotal area of research recently. The ability to visualize and comprehend the metabolic processes of cancer holds immense clinical... (Review)
Review
Cancer metabolism has emerged as a pivotal area of research recently. The ability to visualize and comprehend the metabolic processes of cancer holds immense clinical value, particularly in the diagnosis of malignant tumors and the assessment of treatment responses. Deuterium Metabolic Imaging (DMI), as a robust, simple, and versatile MR spectroscopic imaging tool, demonstrates promise in tumor diagnosis and treatment efficacy assessment. This review explored the latest developments and applications of DMI in oncology across various tumor metabolic axes, with a specific emphasis on its potential for clinical translation. DMI offers invaluable insights into tumor biology, treatment responses, and prognostic outcomes. Notably, DMI can identify early responses to immunotherapy, a prominent area of current research interest. In conclusion, DMI harbors the potential to evolve into a convenient and efficient imaging technique in clinical practice, thereby advancing precision medicine and improving the diagnosis and evaluation of cancer treatments.
PubMed: 38090478
DOI: 10.3389/fonc.2023.1285209 -
The Journal of Physical Chemistry. B Sep 2023DO is commonly used as a solvent instead of HO in spectroscopic studies of proteins, in particular, in infrared and nuclear-magnetic-resonance spectroscopy. DO is... (Review)
Review
DO is commonly used as a solvent instead of HO in spectroscopic studies of proteins, in particular, in infrared and nuclear-magnetic-resonance spectroscopy. DO is chemically equivalent to HO, and the differences, particularly in hydrogen-bond strength, are often ignored. However, replacing solvent water with DO can affect not only the kinetics but also the structure and stability of biomolecules. Recent experiments have shown that even the mesoscopic structures and the elastic properties of biomolecular assemblies, such as amyloids and protein networks, can be very different in DO and HO. We discuss these findings, which probably are just the tip of the iceberg, and which seem to call for obtaining a better understanding of the HO/DO-isotope effect on water-water and water-protein interactions. Such improved understanding may change the differences between HO and DO as biomolecular solvents from an elephant in the room to an opportunity for protein research.
Topics: Water; Proteins; Solvents; Isotopes; Deuterium Oxide
PubMed: 37722111
DOI: 10.1021/acs.jpcb.3c04385 -
Journal of the American Chemical Society Nov 2023Tandem mass spectrometry (MS/MS) using fragmentation has become one of the most effective methods for gaining sequence and structural information on biomolecules....
Tandem mass spectrometry (MS/MS) using fragmentation has become one of the most effective methods for gaining sequence and structural information on biomolecules. Ion/ion reactions are competitive reactions, where either proton transfer (PT) or electron transfer (ET) can occur from interactions between multiply charged cations and singly charged anions. Utilizing ion/ion reactions with fluoranthene has offered a unique method of fragment formation for the structural elucidation of biomolecules. Fluoranthene is considered an ideal anion reagent because it selectively causes electron-transfer dissociation (ETD) and minimizes PT when interacting with peptides. However, limited investigations have sought to understand how fluoranthene─the primary, commercially available anion reagent─interacts with other biomolecules. Here, we apply deuterium labeling to investigate ion/ion reaction mechanisms between fluoranthene and divalent, metal-adducted carbohydrates (Ca, Mg, Co, and Ni). Deuterium labeling of carbohydrates allowed us to observe evidence of hydrogen/deuterium exchange (HDX) occurring after ion/ion dissociation reactions. The extent of deuterium loss is dependent on several factors, including the physical properties of the metal ion and the fragment structure. Based on the deuterium labeling data, we have proposed ETD, PTD, and intermolecular PT─also described as HDX─mechanisms. This research provides a fundamental perspective of ion/ion and ion/molecule reaction mechanisms and illustrates properties that impact ion/ion and ion/molecule reactions for carbohydrates. Together, this could improve the capability to distinguish complex and heterogeneous biomolecules, such as carbohydrates.
Topics: Deuterium; Tandem Mass Spectrometry; Protons; Carbohydrates; Anions; Deuterium Exchange Measurement
PubMed: 37874934
DOI: 10.1021/jacs.3c05793 -
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