We report the generation of gas-phase riboguanosine radicals that were tagged at ribose with a fixed-charge 6-(trimethylammonium)hexane-1-aminocarbonyl group. The radical generation relied on ...electron transfer from fluoranthene anion to noncovalent dibenzocrown-ether dication complexes which formed nucleoside cation radicals upon one-electron reduction and crown-ether ligand loss. The cation radicals were characterized by collision-induced dissociation (CID), photodissociation (UVPD), and UV–vis action spectroscopy. Identification of charge-tagged guanosine radicals was challenging because of spontaneous dissociations by loss of a hydrogen atom and guanine that occurred upon storing the ions in the ion trap without further excitation. The loss of H proceeded from an exchangeable position on N-7 in guanine that was established by deuterium labeling and was the lowest energy dissociation of the guanosine radicals according to transition-state energy calculations. Rate constant measurements revealed an inverse isotope effect on the loss of either hydrogen or deuterium with rate constants k H = 0.25–0.26 s–1 and k D = 0.39–0.54 s–1. We used time-dependent density functional theory calculations, including thermal vibronic effects, to predict the absorption spectra of several protomeric radical isomers. The calculated spectra of low-energy N-7-H guanine-radical tautomers closely matched the action spectra. Transition-state-theory calculations of the rate constants for the loss of H-7 and guanine agreed with the experimental rate constants for a narrow range of ion effective temperatures. Our calculations suggest that the observed inverse isotope effect does not arise from the isotope-dependent differences in the transition-state energies. Instead, it may be caused by the dynamics of post-transition-state complexes preceding the product separation.
Copper and titanium nanoclusters in Ar and in Ar+O2 gas mixtures were prepared using a magnetron based gas aggregation cluster source designed for Ultra High Vacuum operation. A considerable ...influence of oxygen addition on the formation of clusters was observed even at oxygen-to-argon admixture levels of the order of 1:1000. A quadrupole mass filter determined nanocluster size distribution while the total deposition rate was determined by quartz crystal measurements.
Kainate receptors play a crucial role in mediating synaptic transmission within the central nervous system. However, the lack of selective pharmacological tool compounds for the GluK3 subunit ...represents a significant challenge in studying these receptors. Recently presented compound 1 stands out as a potent antagonist of GluK3 receptors, exhibiting nanomolar affinity at GluK3 receptors and strongly inhibiting glutamate‐induced currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. This study presents the synthesis of two potent GluK3‐preferring iodine derivatives of compound 1, serving as precursors for radiolabelling. Furthermore, we demonstrate the optimisation of dehalogenation conditions using hydrogen and deuterium, resulting in 2H‐1, and demonstrate the efficient synthesis of the radioligand 3H‐1 with a specific activity of 1.48 TBq/mmol (40.1 Ci/mmol). Radioligand binding studies conducted with 3H‐1 as a radiotracer at GluK1, GluK2, and GluK3 receptors expressed in Sf9 and rat P2 membranes demonstrated its potential applicability for selectively studying native GluK3 receptors in the presence of GluK1 and 2‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor‐blocking ligands.
Using a dehalogenation strategy, we have effectively labelled a potent GluK3 and GluK1‐preferring competitive kainate receptor antagonist. Radioligand binding studies conducted with 3H‐1 demonstrated applicability for selectively studying native GluK3 receptors in the presence of selective GluK1 and AMPA receptor‐blocking ligands.
A new catalytic enantiospecific approach to the synthesis of epibrassinosteroids (and other polyhydroxylated steroids) regiospecifically labeled by heavy isotopes of hydrogen is reported. ...Chlorocarbonate, efficiently synthesized from α-hydroxy ketone by a reaction with triphosgene, undergoes reductive tritium dechlorination catalyzed by the Pd0/Et3N system, providing 24-3β-3Hepicastasterone and 24-3β-3Hepibrassinolide, respectively, in good yield and with high specific activity (5.8 Ci/mmol; 20% tritium enrichment per molecule).
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Detailed mechanism(s) of the beneficial effects of renal denervation (RDN) on the course of heart failure (HF) remain unclear. The study aimed to evaluate renal vascular responsiveness to angiotensin ...II (ANG II) and to characterize ANG II type 1 (AT
) and type 2 (AT
) receptors in the kidney of Ren-2 transgenic rats (TGR), a model of ANG II-dependent hypertension. HF was induced by volume overload using aorto-caval fistula (ACF). The studies were performed two weeks after RDN (three weeks after the creation of ACF), i.e., when non-denervated ACF TGR enter the decompensation phase of HF whereas those after RDN are still in the compensation phase. We found that ACF TGR showed lower renal blood flow (RBF) and its exaggerated response to intrarenal ANG II (8 ng); RDN further augmented this responsiveness. We found that all ANG II receptors in the kidney cortex were of the AT
subtype. ANG II receptor binding characteristics in the renal cortex did not significantly differ between experimental groups, hence AT
alterations are not responsible for renal vascular hyperresponsiveness to ANG II in ACF TGR, denervated or not. In conclusion, maintained renal AT
receptor binding combined with elevated ANG II levels and renal vascular hyperresponsiveness to ANG II in ACF TGR influence renal hemodynamics and tubular reabsorption and lead to renal dysfunction in the high-output HF model. Since RDN did not attenuate the RBF decrease and enhanced renal vascular responsiveness to ANG II, the beneficial actions of RDN on HF-related mortality are probably not dominantly mediated by renal mechanism(s).
An alternative and robust method for the reduction of carbonyl groups by frustrated Lewis pairs (FLPs) is reported in this paper. With its very mild reaction conditions, good to excellent yields, ...absolute regioselectivity and the non-metallic character of the reagent, it provides an excellent tool for 1H, 2H as well as 3H chemistry. It is a new strategy for the one-pot synthesis of aromatic alcohols selectively labeled with heavy isotopes of hydrogen.
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We report a combined experimental and computational study aimed at elucidating the structure of
N
-terminal fragment ions of the
c
type produced by electron transfer dissociation of photo-leucine ...(L*) peptide ions GL*GGKX. The
c
4
ion from GL*GGK is found to retain an intact diazirine ring that undergoes selective photodissociation at 355 nm, followed by backbone cleavage. Infrared multiphoton dissociation action spectra point to the absence in the
c
4
ion of a diazoalkane group that could be produced by thermal isomerization of vibrationally hot ions. The
c
4
ion from ETD of GL*GGK is assigned an amide structure by a close match of the IRMPD action spectrum and calculated IR absorption. The energetics and kinetics of
c
4
ion dissociations are discussed.
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GHB (γ‐hydroxybutyrate) is not only an endogenously present small molecule but also a clinically prescribed drug for the symptomatic treatment of narcolepsy. However, GHB's mechanism of action ...remains to be uncovered. Within the CNS, GHB targets both GABAB receptors and a pharmacologically distinct population of high‐affinity binding sites with unknown molecular identity. HOCPCA (3‐hydroxycyclopent‐1‐enecarboxylic acid) is a structural analog of GHB selectively targeting GHB high‐affinity binding sites. Here, we discuss the usefulness of 3H‐ and 11C‐labeled HOCPCA as radioligands for selectively probing GHB high‐affinity binding sites and their application in drug discovery. As such, 3HHOCPCA's exceptional affinity and selectivity makes it an indispensable tool in drug discovery, and its utility has been demonstrated in, for example, homogenate binding studies, in vitro as well as ex vivo autoradiography. Moreover, the successful synthesis of 11CHOCPCA is a starting point for further ligand development for future in vivo investigations of GHB high‐affinity binding sites.
The usefulness of radiolabeled HOCPCA for selectively labeling brain‐specific GHB high‐affinity binding sites both in vitro and in vivo is reviewed. 3HHOCPCA proves to be a highly useful tool to study GHB's pharmacology.
Reliable production of nanoparticles (NPs) by magnetron sputtering in a gas aggregation source (GAS) is of great interest because of many potential applications. The size, shape, or structure of NPs ...can be tuned by the operational parameters of the GAS. In this study, fabrication of copper (Cu) NPs is investigated dependent on the magnetron magnetic field (MF)–a not much studied parameter. Decrease of the MF from 83 to 35 mT results in changes in the shape and size distribution of the NPs. MF also strongly affects the NPs deposition rate (DR). Electromagnetic trapping of the NPs in the vicinity of the magnetron target is proposed to be responsible for the changes in DR and polydispersity. The highest DR was reached at 45 mT.
The magnetron magnetic field (MF) has a strong influence on the formation and growth of copper nanoparticles (Cu NPs) during the fabrication in a gas aggregation source. The size, shape, and deposition rate of Cu NPs is affected when decreasing the MF from 83 to 35 mT (the magnet‐to‐target distance of 0–6 mm).
Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine ...kinase–type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared d-HisB24, GlyB31, TyrB32-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of d-HisB24, GlyB31, TyrB32-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of d-HisB24, GlyB31, TyrB32-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.
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