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Iodine(I) carboxylates have been explored as iodination reagents, but the role of the carbonyl group in promoting such reactivity remains poorly understood. Here, the authors prepare iodine(I) pnictogenates and find that they excel as iodination reagents in comparison to iodine(I) carboxylates.
ATP-binding cassette transporter ABCB1 is known to be involved in drug resistance in cancer treatment, however, current ABCB1 inhibitors have not been successful in clinical trials due to their potential cytotoxicity. Here, the authors hypothesize that potential ABCB1 substrates in bats could act as competitive inhibitors against ABCB1 in humans, and identify the tryptophan structure as a promising lead structure for the development of non-toxic ABCB1 inhibitors.
Criegee intermediates such as CH2OO play an important role in tropospheric oxidation models through their reactions with atmospheric trace chemicals. Here, the authors develop a global full-dimensional potential energy surface for the CH2OO + SO2 system, reveal how the reaction happens step by step using quasi-classical trajectory simulations, to show a new direct stripping pathway forming the main products CH2O and SO3 and a new product channel.
The propargyl radical (C3H3) self-reaction is a pivotal step in the formation of benzene in nature, but experimental validation for the complex reaction channels and products is challenging to obtain. Here, the authors produce propargyl radicals in a flow tube and report the branching ratios of eight identified C6H6 isomers in the propargyl self-reaction using isomer-selective threshold-photoelectron spectroscopy.
Hypervalent iodine(III) reagents show promising properties in organic synthesis, however, the application of nitrooxyl (O2NO)-containing I(III) reagents remains underexplored. Here, the authors report the synthesis of a benziodazole-type O2NO-I(III) reagent, which can be applied to the synthesis of furazan heterocycles as a nitrating agent, by reaction with β-monosubstituted enamines via a copper-catalyzed radical nitration/cyclization/dehydration cascade.
Benzothiazinones (BTZs) are being developed as new antibiotics against the infection caused by Mycobacterium tuberculosis, however, BTZs can undergo an in vivo biotransformation to hydride-Meisenheimer complexes (HMC). Here, the authors show that HMC formation can be modulated by C-6 substitution of BTZ.
Boronate-based ß-lactamase inhibitors play an important role in treating multidrug-resistant bacteria infection, however, the molecular mechanism of inhibition remains unclear. Here, the authors use time-resolved serial crystallography to investigate the binding process by using boric acid as a model against β-lactamase CTX-M-14, revealing the binding to the active site serine within 80–100 ms, a subsequent 1,2-diol boric ester formation with glycerol within 100–150 ms, as well as the displacement of the sulfate anion in the active site.
Biomolecular condensates show distinct physicochemical properties that may affect the rate of enzymatic activity and control cellular redox reactions, however, their influence on the other types of chemical reaction remains underexplored. Here, the authors use reactive Martini simulations to probe the non-enzymatic macrocyclization reaction of benzene-1,3-dithiol in the presence of peptide condensates.
Geometric deep learning methods have the advantage of being expressive, while denoising diffusion probabilistic models have great generative power. Here, the authors introduce a geometry-complete diffusion model for effective 3D molecule generation for specific protein pockets that can also consistently optimize the geometry and chemical composition of existing 3D molecules for molecular stability and property specificity
Nuclear receptor-related 1 (Nurr1) is a promising candidate target for neurodegenerative disease treatment, however, the validation of their therapeutic potential remains underexplored due to a lack of high-quality chemical tools. Here, the authors develop Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing, exhibiting nanomolar potency and efficient cellular target engagement, showing their potential as lead and chemical tools.
Uridine diphosphate-dependent glycosyltransferases (UGTs) play a vital role in the biocatalytic glycosylation of phenolic compounds, however, UGT-catalyzed transformations remain not well-characterized. Here, the authors investigate new members of UGT72 and UGT84 families, revealing their specific reactivity and regio-selectivity on selected polyphenolic substrates.
Artificial cells are promising models to study intercellular communications, however, the chemical communication between populations of artificial cells remains underexplored. Here, the authors show the exchange of proteins between distinct populations of coacervate-based artificial cells by regulation of protein affinity and competitive binding with hub protein 14-3-3.
Pyridine is an essential structural motif in medicinal chemistry and shows a wide range of bioactivities based on its substitution patterns, however, the meta-substitution of pyridine remains challenging. Here, the authors develop the synthesis of dissymmetric di-meta-substituted pyridines from 3-formyl(aza)indoles through the in situ generation of enamines via resonance-assisted hydrogen bonding, showcasing various synthetic applications in medicinal chemistry.
Histone methylation by histone lysine methyltransferases (HKMTs) is a vital post-translational modification regulating gene expression, however, selective mapping of methylation by proteomics analysis remains challenging. Here, the authors develop a heavy co-factor analogue 13CD3-BrSAM for HKMT DOT1L that can selectively heavy label target substrates, and map their methylation by proteomics.
Genetically encoded libraries are key technologies in peptide drug discovery, and the constraint of peptide structures by macrocyclization is known to improve their therapeutic properties. Here, the authors report biocompatible bismuth and arsenic bicyclization of genetically encoded peptide libraries displayed on phages. The resulting bicycles show improved binding affinity over their linear counterparts.
The binding and phosphorylation of serine–arginine-rich (SR) proteins by SR protein kinases (SRPKs) is essential to regulate target gene expression, however, the efficient inhibition of this interaction and phosphorylation remains underexplored. Here, the authors develop a covalent inhibitor that targets the lysine residue within the SRPK-specific docking groove, to block interaction and phosphorylation of the prototypic SR protein SRSF1.
Building stimuli-responsive supramolecular materials enables spatiotemporal control over complex systems, and is a promising strategy for a range of applications. Here, mixing adenosine 5’-triphosphate (ATP) with an azobenzene-guanidium compound possessing photodependent nucleotide binding affinity is shown to result in the spontaneous photo-reversible self-assembly of these compounds into micrometer-sized fluorescent aggregates that display dynamic responses to several chemical, physical and biological stimuli.
Transition metal dichalcogenides exhibit rich polymorphism, making them promising candidates for superconductors, topological insulators, and electrochemical catalysts. Here, the authors study the metallization of non-hydrostatically compressed ZrS2 up to 45.8 GPa and find that a new high-pressure phase forms under deviatoric stress.
A key strategy for minimizing our reliance on precious metal catalysts is to increase the fraction of surface atoms and improve the metal—support interface. Here, the authors develop a system in which nanoscale morphological changes in the catalyst are monitored and directly linked with the selectivity of the CO2 electroreduction reaction.
Strained carbo- and heterocycles are essential motifs in medicinal chemistry and drug discovery, however, their selective functionalization remains challenging. Here, the authors develop a one-pot strategy to access stereo-defined trisubstituted azetidines, cyclobutanes, and five-membered carbo- and heterocycles based on the polar radical crossover of borate derivatives.