Articles in 2023

Liquid–liquid phase separation (LLPS) within cells is a captivating phenomenon known to aid the organization of cellular components; however, its complex kinetics have remained a puzzle. Now, a new study elucidates the crosstalk between the phase state of an encapsulating membrane and LLPS dynamics.

Given the fraught history of fluorine, Michelle Francl wonders what made medicinal chemists consider fluorine derivatives?

Cysteine bioconjugation is an important method to modify biomolecules, but synthetic efforts to diversify reactive warheads and the low reactivity of introducible linchpins often impede application in biological laboratories. Now, a thianthrenium-based reagent permits site-selective installation of episulfonium on biomacromolecules, enabling one-step addition of bioorthogonal nucleophiles and further applications in quantitative proteomics and cross-linking.

In contrast to photothermal therapy requiring high powers over extended times and photodynamic therapy being abrogated by inhibitors of reactive oxygen species, actuation of vibronic modes in single molecules—molecular jackhammers—can now induce efficient cancer cell death. Here, the mechanical disassembly of cell membranes is characterized as the underlying mechanism by which this vibronic-driven action promotes necrotic cell death.

As the need for specific fluorescent probes that enable high sensitivity and super-resolution imaging experiments continues to grow, it is imperative to develop new, well-characterized methods to modulate the emission of fluorophores. Now, a general platform affords visible-to-NIR fluorogenic fluorophores by engineering a simple cyclization event into cyanine dyes.

Current proteolysis-targeting chimeras can promote the ubiquitination and subsequent degradation of both target and off-target proteins by inducing their respective proximity with the cereblon ubiquitin ligase. Now, by developing and deploying an off-target profiling platform, ‘bumped proteolysis-targeting chimeras’ can maintain on-target degradation efficacy with reduced off-targets.

The study of disordered materials poses numerous challenges, and computational approaches have proved useful to supplement and support structural experiments. Now, an abstract computational model has been used to study the structure of amorphous calcium carbonate, providing mechanistic insights into the emergence of the disordered phase as well as its atomic-level configurations.

Orthogonal click reactions enable the rapid assembly of molecules of all sizes. Now, it has been shown that a nitrile, an allene, a diborane and a hydrazine or aniline can be catalytically merged in a click process that is orthogonal to SuFEx and CuAAC, delivering fluorescent linkages.

Current electrochemical-based protein labelling methods suffer from limited site-selectivity and off-target reactivity owing to required radical/electrophilic reagents. Now an electrochemical strategy enables chemoselective labelling of proteins at a site-specifically incorporated 5-hydroxytryptophan residue using aromatic amines as coupling partners. This approach works on various proteins, including a full-length antibody, and is compatible with established click reactions.

Robust protocols for the synthesis of chiral α-tertiary amino acids remain scarce due to the challenge of constructing congested tetrasubstituted stereocentres. Now a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides has been developed, forming diverse chiral α-tertiary amino esters with high enantioselectivity and excellent functional group tolerance.

The umpolung functionalization of imines bears vast synthetic potential, but polarity inversion is less efficient compared with the carbonyl counterparts. Now, an alternative strategy exploiting chiral phosphoric acid catalytic aromatization has been developed, affording structures possessing a central chirality or a stereogenic C–N axis with high efficiency and enantiocontrol.

Methods for transition-metal-catalysed enantioselective C(sp³)–S bond construction are underdeveloped. Now, by taking advantage of the biomimetic radical homolytic substitution manifold, the copper-catalysed enantioconvergent C(sp³)–S cross-coupling of racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles has been realized. This reaction provides access to an array of α-chiral alkyl organosulfur compounds.

Borenium ions have traditionally served as main group (pre-)catalysts, and their use in materials-related applications have been limited by their instability. Now, a series of fully π-conjugated azaboraacenium ions derived from carbodicarbene have been developed that exhibit high air and moisture stability with full colour-tunable luminescence. Furthermore, these azaboraacene cations mimic the electronic structures of higher-order carbonaceous acenes while featuring enhanced resistance to photo-oxidation.

Light-induced azobenzene cis/trans isomerization has been extensively investigated, but the mechanical strength of its cis/trans structure is not well understood. Now it has been shown that cis azobenzene is mechanically less stable than the trans isomer due to its regiochemical structure, as revealed by single-molecule force spectroscopy.

Activation of H₂ by a metal–olefin complex is characterized experimentally and computationally using a nickel pincer complex, showing that the reaction proceeds via a direct ligand-to-ligand hydrogen transfer mechanism. An application of this cooperative H₂-activation mechanism is demonstrated in the nickel-catalysed semihydrogenation of diphenylacetylene.

Enzyme-initiated polymerization-induced self-assembly has been used to generate various biomimetic structures. Now, myoglobin’s activity is used for biocatalytic polymerization-induced self-assembly to generate vesicular artificial cells. As various cargoes can be encapsulated during polymerization, these artificial cells are capable of protein expression and can act as microreactors for distinct enzymatic reactions.

Many natural products are produced by non-ribosomal peptide synthetases in an assembly-line fashion. How these molecular machines orchestrate the biochemical sequences has remained elusive. It is now understood that an extended-conformation ensemble is needed to coordinate chemical-transformation steps whereas the biosynthesis directionality is driven by the enzyme’s innate conformational free energies.

Fluoroalkyl fragments are ubiquitous motifs in pharmaceuticals and agrochemicals, but their introduction to a given molecule typically involves expensive or difficult-to-handle reagents. Now, the photocatalysed hydrofluoroalkylation of alkenes has been achieved using simple and readily available fluoroalkyl carboxylic acids.