Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules.

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.

Ruthenium-Catalyzed Deuteration of Aromatic Carbonyl Compounds with a Catalytic Transient Directing Group.

Invited for the cover of this issue are Helfried Neumann, Matthias Beller and co-workers at the Leibniz-Institut für Katalyse e. V., Rostock and Hangzhou Normal University. The image depicts "the case of ketone deuteration" being solved by Sherlock Holmes. Read the full text of the article at 10.1002/chem.202100468.

Ruthenium-Catalyzed Deuteration of Aromatic Carbonyl Compounds with a Catalytic Transient Directing Group.

A novel ruthenium-catalyzed C-H activation methodology for hydrogen isotope exchange of aromatic carbonyl compounds is presented. In the presence of catalytic amounts of specific amine additives, a transient directing group is formed in situ, which directs selective deuteration. A high degree of deuteration is achieved for α-carbonyl and aromatic ortho-positions. In addition, appropriate choice of conditions allows for exclusive labeling of the α-carbonyl position while a procedure for the preparation of merely ortho-deuterated compounds is also reported. This methodology proceeds with good functional group tolerance and can be also applied for deuteration of pharmaceutical drugs. Mechanistic studies reveal a kinetic isotope effect of 2.2, showing that the C-H activation is likely the rate-determining step of the catalytic cycle. Using deuterium oxide as a cheap and convenient source of deuterium, the methodology presents a cost-efficient alternative to state-of-the-art iridium-catalyzed procedures.

Manganese-catalyzed selective C-H activation and deuteration by means of a catalytic transient directing group strategy.

A novel manganese-catalyzed C-H activation methodology for selective hydrogen isotope exchange of benzaldehydes is presented. Using D2O as a cheap and convenient source of deuterium, the reaction proceeds with excellent functional group tolerance. High ortho-selectivity is achieved in the presence of catalytic amounts of specific amines, which in situ form a transient directing group.

A Novel NAD-RNA Decapping Pathway Discovered by Synthetic Light-Up NAD-RNAs.

The complexity of the transcriptome is governed by the intricate interplay of transcription, RNA processing, translocation, and decay. In eukaryotes, the removal of the 5'-RNA cap is essential for the initiation of RNA degradation. In addition to the canonical 5'-N7-methyl guanosine cap in eukaryotes, the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD) was identified as a new 5'-RNA cap structure in prokaryotic and eukaryotic organisms. So far, two classes of NAD-RNA decapping enzymes have been identified, namely Nudix enzymes that liberate nicotinamide mononucleotide (NMN) and DXO-enzymes that remove the entire NAD cap. Herein, we introduce 8-(furan-2-yl)-substituted NAD-capped-RNA (FurNAD-RNA) as a new research tool for the identification and characterization of novel NAD-RNA decapping enzymes. These compounds are found to be suitable for various enzymatic reactions that result in the release of a fluorescence quencher, either nicotinamide (NAM) or nicotinamide mononucleotide (NMN), from the RNA which causes a fluorescence turn-on. FurNAD-RNAs allow for real-time quantification of decapping activity, parallelization, high-throughput screening and identification of novel decapping enzymes in vitro. Using FurNAD-RNAs, we discovered that the eukaryotic glycohydrolase CD38 processes NAD-capped RNA in vitro into ADP-ribose-modified-RNA and nicotinamide and therefore might act as a decapping enzyme in vivo. The existence of multiple pathways suggests that the decapping of NAD-RNA is an important and regulated process in eukaryotes.

Peptide-ß-lactam Inhibitors of Dengue and West Nile Virus NS2B-NS3 Protease Display Two Distinct Binding Modes.

The ß-lactam ring represents a valuable moiety that can induce covalent binding of an inhibitor to its target. In this study, we explored di- and tripeptides with ß-lactam electrophilic warheads as inhibitors of dengue and West Nile virus NS2B-NS3 protease. Tripeptides with a (3S)-ß-lactam moiety displayed the highest activity, with IC50 and EC50 values in the lower micromolar range in biochemical and cellular assays. The activity against dengue protease was in general higher than against West Nile virus protease. The compounds were inactive against the off-targets thrombin and trypsin. Liquid chromatography-mass spectrometry experiments revealed that tripeptide-ß-lactam inhibitors bind to the protease in two distinct binding modes. Only one binding mode leads to a covalent, but reversible, interaction of the ß-lactam ring with the catalytic serine, followed by release of the inhibitor with opened ß-lactam ring. The other binding mode leads to the cleavage of the peptide backbone. This observation provides the first experimental evidence that benzyloxyphenylglycine in flaviviral protease inhibitors is positioned in the prime site of the enzyme.

Deprotonation, insertion and isomerisation in the post-functionalisation of tris-pyridyl aluminates.

Post-functionalisation of the aluminate anion [EtAl(6-R-2-py)3]- (6-R-2-py = 6-R-2-pyridyl, R = Me or Br) can be accomplished via nucleophilic addition of the pyridyl groups to the electrophilic C[double bond, length as m-dash]O group of aldehydes (RCH[double bond, length as m-dash]O) or by deprotonation of carboxylic acids (RCO2H). NMR spectroscopic and crystallographic studies show how 6-Me-2-py groups can detect chirality and reveal a new aspect of isomerism.

Modifying the donor properties of tris(pyridyl)aluminates in lanthanide(ii) sandwich compounds.

The coordination ability of tris(pyridyl)aluminates can be modified by the steric and electronic character of substituents at the 6-positions of their pyridyl rings. Whereas [EtAl(6-Me-2-py)3]- (1) coordinates strongly to lanthanide(ii) ions [Eu(ii) and Yb(ii)], [EtAl(6-Br-2-py)3]- (2) forms much weaker complexes, and [EtAl(6-CF3-2-py)3]- does not coordinate at all. The modification of the donor ability of these ligands is investigated by solid-state studies of the Ln(ii) sandwich compounds and by competitive coordination studies in solution.

Hospital Readmissions from Patients' Perspectives.

OBJECTIVES: Healthcare expenditures in the United States have increased exponentially and hospital care accounts for one-third of these costs. Approximately 18% of hospitalized Medicare beneficiaries are being readmitted to the hospital within 30 days. Engaging patients in the discharge process can help better identify patients' postdischarge needs and implement more effective readmission prevention strategies. The objective of our study was to identify the factors that contribute to hospital readmission as seen from patients' perspectives in a large urban community hospital. METHODS: We evaluated all consecutive, unplanned readmissions to the hospitalist service within 30 days of discharge, using the STate Action on Avoidable Rehospitalizations diagnostic worksheet with face-to-face patient interviews and retrospective chart reviews. RESULTS: During the study period, 80 patients were readmitted within 30 days of their discharge, with 28 of them having more than one readmission. The mean age was 50.8 ± 18.3 years. Of the 80 patients, 51% were men and 51% were black. Sickle cell disease was the leading diagnosis (11.3%) in both index admissions and readmissions. Patient interviews identified some modifiable risk factors for readmissions such as the inability to obtain medications or schedule follow-up appointments as well as problems related to transportation, housing, and social support. Despite clear discharge planning and patient understanding of the plan being recorded at discharge, almost one-third of patients appeared to lack the ability to self-manage symptoms and understand the disease process. CONCLUSIONS: Our study demonstrated that engaging patients in discharge planning can help identify barriers within the process. Improvements in socioeconomic/environmental layers of population health have the potential to prevent hospitalizations and readmissions in the long term.