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Unlocking NIR-II Photoluminescence in 2D Copper Tetrasilicate Nanosheets Through Flame Spray Pyrolysis
No full textExpanding fluorescence bioimaging into the second near-infrared spectrum (NIR-II, 1000-1700 nm) unlocks advanced possibilities for diagnostics and therapeutics, offering superior tissue penetration and resolution. Two-dimensional copper tetrasilicate (CTS) pigments (MCuSi4O10, M = Ca, Sr, Ba) are known for their brightness and stability, yet synthetic challenges have curbed their integration into bioimaging. Here, we introduce flame-spray-pyrolysis (FSP) as a versatile and scalable synthesis approach to produce ultra-bright, metastable CTS nanosheets (NS) by annealing multi-element metal oxide nanoparticles into 2D crystals. Group-II ion incorporation shifts emission into the NIR-II range, with Ba0.33Sr0.33Ca0.33CuSi4O10 peaking at 1007 nm, while minor Mg-doping induces a hypsochromic shift and extends fluorescence lifetimes. The engineered CTS achieve quantum yields up to 34%, supporting NS high-frame-rate imaging (>200 fps). These unique properties enable CTS-NS to serve as powerful contrast agents for super-resolution NIR bioimaging, demonstrated in vivo through transcranial microcirculation mapping and macrophage tracking in mice using diffuse optical localization imaging (DOLI). This pioneering synthesis strategy unlocks wavelength-tunable NS for advanced NIR-II bioimaging applications
Carbene-destabilised stannylenes: Accessing selective C(sp3)–H bond scission at the steric limit
No full textThe ubiquity of N-heterocyclic carbenes (NHCs) in diverse areas of chemical research typically arises from their potent stabilising capabilities and role as innocent spectators to stabilise otherwise non-bottleable compounds and complexes. This has, until now, been particularly true for NHC-stabilised stannylenes, with no exceptions reported thus far. Herein, we demonstrate that the combination of heteroleptic terphenyl-/amido-based stannylenes and tetra-alkyl substituted NHCs renders the corresponding NHC-ligated stannylenes destabilised, yet isolable. In solution, this induces sterically controlled inter- and intramolecular C(sp3)–H activation processes to provide stannylene metallocycles of select nuclearity
Intermolecular Formal [8+3] Cycloaddition of Azaheptafulvene with Bicyclo[1.1.0]butanes Promoted by Lewis Acids
No full textAzaheptafulvenes reacting with bicyclo[1.1.0]butanes (BCBs) through FeCl3 or Sc(OTf)3-promoted formal [8+3] cycloaddition reactions to furnish Nitrogen-containing polycyclic compounds has been developed for the first time. This new reaction tolerated a wide range of azaheptafulvenes and BCBs. Furthermore, the amplification experiments and synthetic transformations of the cycloaddition compounds further highlighted its practicality
SpaceHASTEN: A structure-based virtual screening tool for non-enumerated virtual chemical libraries
No full textGiven the size of the drug discovery relevant chemical space, working with fully enumerated
compound libraries (especially in 3D) is unfeasible. Non-enumerated virtual chemical spaces
are a practical solution to this issue; where compounds are described as building blocks
which are then connected by rules. One concrete example of such is the BioSolveIT chemical
spaces file format (.space). Tools to search these space-files exist that are using ligand-based
methods including, 2D fingerprint similarity, substructure matching, and fuzzier similarity
metrics such as FTrees. However, there is no software available that enables the screening of
these spaces using molecular docking. Here, a tool, called SpaceHASTEN, was developed on
top of SpaceLight, FTrees, LigPrep, and Glide to allow efficient virtual screening of nonenumerated
chemical spaces. SpaceHASTEN was validated using three public targets picked
from the DUD-E dataset. It was able to retrieve a large number of diverse and novel high
scoring compounds (virtual hits) from non-enumerated chemical spaces of billions of
molecules, after docking a few million compounds. The software can be freely used and is
available from http://github.com/TuomoKalliokoski/SpaceHASTEN.
Keywords
Backbone Nitrogen Substitution Restricts the Conformation of Glycine Residues in Protein β-Turns
No full textGlycine adopts backbone conformations that are generally inaccessible to other amino acids, but specifying a particular conformation remains challenging. Inspired by studies of small-molecule models, we hypothesized that substituting the alpha carbon with nitrogen would bias glycine toward specific β-turn conformations, which we confirmed through biophysical analysis of backbone-modified peptides
Bloch-Siegert shifted correlations in solution NMR spectroscopy
No full textWe further develop the concept of refocusing scalar couplings in solution NMR spectroscopy by means of 2-field correlations as recently presented in doi:10.26434/chemrxiv-2024-r9tgw. We show that Bloch-Siegert shifts can be used as fictitious secondary fields for such purpose. This allows correlations to be made with data acquired in a single external magnetic field. A homonuclear 2D correlation spectroscopy experiment can be easily modified so as to include these rf-driven shifts in the indirect dimension. Furthermore, the inclusion of such effects in window-acquired 1D spectra allows for synthetic homonuclear decoupling procedures to be performed
Quantification of arginine rich cyclic cell-penetrating peptide-lipid-conjugates using trifluoracetic acid-based UPLC-MS/MS analysis
No full textLipid-based drug delivery systems can be surface modified by lipid-conjugates of the pertinent substance. Prominent modifica-tions include arginine-rich cell-penetrating peptides (CPP). Toxicokinetic evaluation of these lipid-conjugates is important during pre- and clinical development of drug-delivery formulations. Due to their amphiphilic character and high number of basic amino acid residues, lipid-conjugates of CPP exhibit challenging characteristics in regard to their plasma bioanalysis with LC-MS/MS instruments. These especially include challenging chromatography and minimal extraction recovery, and, due to large numbers of basic amino acids and the resulting immobility of protons, resistance against collision-induced dissociation. We developed a surro-gate quantification of a CPP-lipid-conjugate relying on elimination of the lipid-part by phospholipase D digestion. Chromatograph-ic separation was only feasible with trifluoro acetic acid (TFA) based mobile phases. Ion suppression caused by TFA was reversed by post-column addition of aqueous ammonia. Efficient extraction of the surrogate peptide fragment was achieved by protein precipitation with TFA. This enabled the highly sensitive quantification of the CPP-lipid-conjugate in plasma in the low picomolar range (lower limit of quantification of 0.1 ng/mL; 34 pM). The assay was validated according to the pertinent guidelines of the FDA and EMA on bioanalytical method validation and applied to the determination of intravenous pharmacokinetics of the CPP-lipid-conjugate in Beagle dogs. The established strategy can be used as a general approach to the bioanalysis of amphiphilic lipid-conjugates and especially the TFA-based UPLC-MS/MS analysis for arginine rich peptides and other substances with challenging chromatographic characteristics
Large Language Models in Drug Discovery: A Survey
No full textDrug Discovery is a very lengthy and resource-consuming process. However, a variety of
advanced Artificial Intelligence (AI) and Deep Learning (DL) techniques are being utilized to
accelerate and advance DD, such as Large Language Models (LLMs). This survey is in aim of
discovering and comparing the currently available LLMs, their methodologies, used datasets, and
the different tasks they are aiding in in the DD process, in particular; de novo drug design, drug target interaction prediction, masked language models, variational auto encoders, binding affinity
prediction, drug repurposing, molecular optimization, activity prediction, contrastive learning for
drug-target interaction prediction, and other miscellaneous models. This survey gives insights
into future directions and potential in this area
An Improved P(V) Oligonucleotide Synthesis Platform
No full textThree critical advances in simplifying the adoption of P(V)-based stereopure, phosphorothioate-containing oligonu-cleotide synthesis are reported. A more inexpensive phosphorus-sulfur incorporation reagent (Ψ-Br) is introduced, a robust linker system was developed, and a systematic study of common nucleobase protecting groups performed to significantly reduce the barrier to adoption of this technology
Engineering macroporous carbon film support for freestanding Fe-N-C cathode at high current densities
No full textAs the oxygen reduction reaction (ORR) kinetics account for the largest share of performance losses for fuel cells, most research in platinum group metal (PGM)-free catalysts prioritize on improving the activity of catalysts by maximizing the active site density and by engineering of the local coordination environment of the active sites to meet the activity targets. Thereby, the mass-transport capabilities of the catalyst is usually neglected at early stages of catalyst development. In this work, the reverse approach is taken: A carbon film support with an interconnected macropore network is designed for improved mass transport. Carbon precursors mesophase pitch and polyvinylalcohol (PVA) are combined with the macropore template polystyrene (PS) spheres in a ball-milling process to form a slurry for casting the film which is subsequently carbonized in different atmospheres to tune the micropore volume and combined with a model FeN4 active site. The macroporous films are thoroughly characterized by means of SEM, N2 sorption, XPS and Mercury Intrusion Porosimetry (MIP) and tested as ORR catalyst support for a model FeN4 active site in a Gas-Diffusion-Electrode (GDE) half-cell, which can operate at high current density conditions. The mass transport properties of film supports with thickness of 30 µm and 70 µm are analysed and compared to a conventional powder catalyst layer based on Vulcan XC 72 powder support. The average overpotentials for powder and film supports at a high current density of 2 A/cm2 are centred in the narrow range of 0.52 V ± 0.03 V, which highlights the competitive mass transport performance of the macroporous film support