A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon‐13. Key to the success of this novel carbon ...isotope labeling technique is the observation that 13C‐labeled NiII‐acyl complexes, formed from a 13CO insertion step with NiII‐alkyl intermediates, rapidly react in less than one minute with 2,2’‐dipyridyl disulfide to quantitatively form the corresponding 2‐pyridyl thioesters. Either the use of 13C‐SilaCOgen or 13C‐COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one‐pot acylation of a series of structurally diverse amines provides the desired 13C‐labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII‐acyl complexes and the disulfide providing a reactive NiIII‐acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon‐11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13C‐labeled liraglutide and insulin degludec, representing two antidiabetic drugs.
The faster the better: Rapid nickel(II)‐mediated thiocarbonylation of alkyl zinc reagents provides an expedient route to activated esters, which can subsequently be exploited for the direct synthesis of aliphatic carboxamides. This process is highly adaptable to carbon isotope labeling, which was illustrated for the synthesis of 13C‐labeled low molecular weight drugs and biopharmaceuticals.
This paper describes the discovery, synthesis, and use of novel water-soluble acylation reagents for efficient and selective modification, cross-linking, and labeling of proteins and peptides, as ...well as for their use in the effective modification of sepharose beads under pH control in aqueous media. The reagents are based on a 2,4-dichloro-6-sulfonic acid phenol ester core combined with a variety of linker structures. The combination of these motifs leads to an ideal balance between hydrolytic stability and reactivity. At high pH, good to excellent conversions (up to 95%) and regioselectivity (up to 99:1 N ε/N α amine ratio) in the acylation were realized, exemplified by the chemical modification of incretin peptides and insulin. At neutral pH, an unusually high preference toward the N-terminal phenylalanine in an insulin derivative was observed (>99:1 N α/N ε), which is up until now unprecedented in the literature for more elaborate reagents. In addition, the unusually high hydrolytic stability of these reagents and their ability to efficiently react at low concentrations (28 μM or 0.1 mg/mL) are exemplified with a hydroxy linker-based reagent and are a unique feature of this work.
Hydrogen Dimers in Giant-planet Infrared Spectra Fletcher, Leigh N.; Gustafsson, Magnus; Orton, Glenn S.
The Astrophysical journal. Supplement series,
03/2018, Volume:
235, Issue:
1
Journal Article
Peer reviewed
Open access
Despite being one of the weakest dimers in nature, low-spectral-resolution Voyager/IRIS observations revealed the presence of (H2)2 dimers on Jupiter and Saturn in the 1980s. However, the ...collision-induced H2-H2 opacity databases widely used in planetary science have thus far only included free-to-free transitions and have neglected the contributions of dimers. Dimer spectra have both fine-scale structure near the S(0) and S(1) quadrupole lines (354 and 587 cm−1, respectively), and broad continuum absorption contributions up to 50 cm−1 from the line centers. We develop a new ab initio model for the free-to-bound, bound-to-free, and bound-to-bound transitions of the hydrogen dimer for a range of temperatures (40-400 K) and para-hydrogen fractions (0.25-1.0). The model is validated against low-temperature laboratory experiments, and used to simulate the spectra of the giant planets. The new collision-induced opacity database permits high-resolution (0.5-1.0 cm−1) spectral modeling of dimer spectra near S(0) and S(1) in both Cassini Composite Infrared Spectrometer observations of Jupiter and Saturn, and in Spitzer Infrared Spectrometer (IRS) observations of Uranus and Neptune for the first time. Furthermore, the model reproduces the dimer signatures observed in Voyager/IRIS data near S(0) on Jupiter and Saturn, and generally lowers the amount of para-H2 (and the extent of disequilibrium) required to reproduce IRIS observations.
Selective modification of peptides and proteins is of foremost importance for the development of biopharmaceuticals and exploring biochemical pathways, as well as other applications. Here, we present ...a study on the development of a general and easily applicable selective method for N-terminal acylation of biomolecules, applying a new type of phenol esters. Key to the success was the development of highly tunable phenol activators bearing in the ortho-position, sulfonic acid or sulfonamide, acting as a steric shield for hydrolysis, and electron-withdrawing groups in the other ortho- and para-position for controlling the reactivity of the activated phenol esters. A library of heptapeptides, testing all 20 natural amino acids positioned at the N-terminal, were acylated in a selective manner at the N-terminus. The majority showed high conversion and excellent N α-selectivity. Several biologically relevant biomolecules, including DesB30 insulin and human growth hormone, could also be modified at the N-terminal in a highly selective way, exemplified by either a fluorophore or a fatty acid sidechain. Finally, taking advantage of the possibility to accurately adjust the reactivity of the phenol esters, we present a potential strategy for the construction of dual active biopharmaceuticals through the employment of a bifunctional acylation linker and demonstrate its use in the creation of a GLP-1 insulin analogue, coupled through the lysine residue of GLP-1 and the N-terminal PheB1 amine of DesB30 insulin.
Positron emission tomography (PET) imaging is used in drug development to noninvasively measure biodistribution and receptor occupancy. Ideally, PET tracers retain target binding and biodistribution ...properties of the investigated drug. Previously, we developed a zirconium-89 PET tracer based on a long-circulating glucagon-like peptide 1 receptor agonist (GLP-1RA) using desferrioxamine (DFO) as a chelator. Here, we aimed to develop an improved zirconium-89-labeled GLP-1RA with increased molar activity to increase the uptake in low receptor density tissues, such as brain. Furthermore, we aimed at reducing tracer accumulation in the kidneys. Introducing up to four additional Zr-DFOs resulted in higher molar activity and stability, while retaining potency. Branched placement of DFOs was especially beneficial. Tracers with either two or four DFOs had similar biodistribution as the tracer with one DFO in vivo, albeit increased kidney and liver uptake. Reduced kidney accumulation was achieved by introducing an enzymatically cleavable Met-Val-Lys (MVK) linker motif between the chelator and the peptide.
Service delivery and solution selling both strive to achieve increased value through co-creation. However, the concept of value co-creation is a macro concept that still lacks precise empirical ...grounding and accurate operationalisation. To uncover the microlevel processes of co-creation, we examined 15 sales cases via the lens of uncertainty management. We used design thinking and actor-network theory to explore how certainty evolves between a seller and the buyer. We argue that the common industrial logic for addressing and tackling customer problems in solution selling, hitherto portrayed as either deductive or inductive, is incomplete. Indeed, our research shows that solution selling and value co-creation both require a different, abductive epistemology to address the uncertainty. Our study also provides an empirical extension to the value co-creation literature.
•Service delivery and solution selling strive towards increased value through co-creation.•Design thinking and actor-network theory is used to explore how certainty evolves between the seller and the buyer.•The industrial logic for addressing customer problems, which has been portrayed as deductive or inductive, is incomplete.•Solution selling and value co-creation require a different, abductive epistemology to encompass uncertainty.
Correct parameterization of the Collision-induced Absorption (CIA) phenomena is essential for accurate modeling of planetary atmospheres. The HITRAN spectroscopic database provides these parameters ...in a dedicated section. Here, we significantly revise and extend the HITRAN CIA data with respect to the original effort described in Richard et al. JQSRT 113, 1276 (2012). The extension concerns new collisional pairs as well as wider spectral and temperature ranges for the existing pairs. The database now contains CIA for N2N2, N2H2, N2CH4, N2H2O, N2O2, O2O2, O2CO2, CO2CO2, H2H2, H2He, H2CH4, H2H, HHe, CH4CH4, CH4CO2, CH4He, and CH4Ar collision pairs. The sources of data as well as their validation and selection are discussed. A wish list to eliminate remaining deficiencies or lack of data from the astrophysics perspective is also presented.
•Update to HITRAN compilation of collision-induced absorption cross-sections•Experimental and theoretical data are thoroughly evaluated•Validated data cast into consistent user-friendly format.•Indispensable tool for atmospheric and astrophysical research•A wish list for future research in this area is provided.
Using an experimental coherent high-resolution X-band radar, we show that micro-Doppler signatures from one or more walking persons can be retrieved off the radar line of sight in a realistic urban ...environment. The off-sightline objects are illuminated by the radar wave multipath wall reflections. Velocity-time diagrams are created for specific walking targets using the short-time Fourier transform. Two scenarios are studied, with one and two persons, respectively, walking along a closed path.
Abstract
Accurate collision-induced absorption profiles for H
2
–He pairs, in the rototranslational band of H
2
, are computed accounting for the full anisotropic interaction potential. The ...calculations are time consuming and complicated compared to those pursued in the isotropic potential approximation. A machine learning approach is implemented in order to produce highly accurate data on a dense frequency grid, by combining data computed in the full calculation with those from the isotropic approximation. Thus an extensive, highly accurate, data base can be obtained for a set of frequencies, temperatures, and ortho-H
2
/para-H
2
fractions, appropriate for use in modeling of planetary atmospheres, in particular of the gas giants.
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