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The confinement of organic chromophores within mesoporous material architectures can exert a considerable alteration on their physico-chemical properties. This study presents a detailed spectroscopic investigation of methylene blue (MB) entrapped in mesoporous polymeric carbon nitrides (mPCNs) with different pore architecturesusing transient absorption spectroscopy (TAS). The spatial confinement of MB molecules results in a prominent change in absorption spectra, characterized by both redshifts and the appearance of additional shoulder peaks, arising from the formation of MB dimers (MB₂) concomitant with a distortion of the MB structure. Upon photoexcitation, entrapped MB molecules exhibit a notable altered excited-state absorption feature, along with a drastic excited-state quenching within 2 ns compared to molecues in bulk solutions. In contrast to the ultrafast quenching of sole MB₂ with a lifetime of ~3.6 ps in highly concentrated solutions, the concentration-dependent quenching behavior of MB aggregates in confined environments suggests the effect is caused by excimers formed in close proximity. The findings of this work highlight the impact of constrained environments and intermolecular interactions on the relaxation pathways of the excited states in photoactive molecules.

The RNA world hypothesis predicts that life started with the development of replicating and catalytically active RNA, which evolved in a process of molecular evolution to increasingly complex chemical structures. RNA is, however, so complex that it has most likely formed from a precursor (proto-RNA) that was more easily accessible in a prebiotic world. Recently, 3-aminoisoxazoles (IO3) were identified as building blocks that can form under prebiotic conditions and can rearrange to give the nucleoside cytidine (C). The present study shows that the constitutional isomer 5-aminoisoxazole (IO5) can undergo the same reaction to give uridine (U). Both compounds (IO3 and IO5), if embedded in RNA, react selectively to C and U, which are the main pyrimidine nucleosides of the genetic system. Importantly, the stereochemical outcome of the IO5 reaction in RNA depends on the neighboring bases. If they are β-configured RNA nucleosides, the reaction proceeds with high selectivity to give exclusively the β-configured U RNA base (anomeric control).

The emergence of thiol-mediated uptake (TMU) as a powerful strategy to penetrate cells calls for the development of practical small-molecule TMU tools for traceless delivery. Toward this goal, esters are explored here as bioreversible linkers between dynamic covalent cascade exchangers accounting for TMU and the protein of interest (POI). The method relies on α-aryl-α-diazoamides that react with carboxylic acids of the POI to form esters that can be enzymatically hydrolyzed inside cells to release the native POI. A two-step protocol is established for bioreversible conjugation of TMU tags to the POI. Despite the small number of tags attached to POIs to prevent isoelectric precipitation, POIs with traceless TMU tags are shown to efficiently enter cells not only in 2D culture but also in 3D spheroids mimicking deep tissue, confirming a key advantage of TMU. Uptake inhibition by various thiol-reactive agents confirms the participation of cell-surface thiols in cell penetration, i. e., the occurrence of TMU.

Structurally characterised U−Sb bonds are rare. Here, the synthesis and characterisation of [U(Tren^DMBS){Sb(H)C(H)(SiMe₃)₂}] (5, Tren^DMBS=N(CH₂CH₂NSiMe₂Bu^t)₃) and [{U(Tren^TIPS)}₂{Sb₃(μ₆-Li)(μ-Li[THF]₂)₃Sb₃}] (6, Tren^TIPS=N(CH₂CH₂NSiPrⁱ₃)₃) are reported. Complex 5 is an unprecedented primary stibinide actinide complex and 6 can be formulated as containing a unique triple decker 20 skeletal-electron distorted closo tricapped Zintl cluster (Sb₃Li₄Sb₃)²⁻ that is analogous to the D_3h closo tricapped trigonal prism form of [Ge₉]²⁻. Quantum chemical calculations emphasise polar U−Sb bonding in 5 and 6, and that viewing (Sb₃Li₄Sb₃)²⁻ as a single unit rather than two distinct but contiguous (Sb₃)³⁻ units, themselves unprecedented in molecular actinide chemistry, is valid due to the presence of three weak (Sb₃)⋯(Sb₃) (3, −1)-bond critical points. Complexes 5 and 6 highlight the challenges of preparing polar U−Sb bonds and the underlying tendency for unpredictable cluster formation with Sb.

Fluorescent flippers have been introduced as small-molecule probes to image membrane tension in living systems. While the hydrophilic headgroup region has been modified extensively for intracellular targeting, little is known about the hydrophobic interfacing with the surrounding membrane. To tackle this challenge, the design, synthesis and evaluation of a glutamine-derived flipper collection is reported. Considering the importance of tension-induced phase separation for tension imaging, this study is focused on how to modulate the distribution of functional flippers between ordered and disordered microdomains. Also of interest was control over intermembrane transfer without loss of function for the specific labeling of plasma and intracellular membranes. Evidence is presented for a two-step insertion mechanism through more accessible disordered domains into better matching ordered domains. This process also explains differences between partition coefficients and bioimaging. It is further demonstrated that interdomain and intermembrane distribution can be regulated by hydrophobic interfacing to control brightness in fluorescence lifetime imaging microscopy and responsiveness to membrane tension. Irreversible partitioning inhibits intermembrane transfer and coincides with internalization into cells. These results demonstrate that hydrophobic interfacing can improve probe performance and provide guidelines on how to proceed.

Protein-ligand interactions are crucial for many cellular processes, with details of the binding mechanism being discussed as essential for biological functions. Interestingly, protein binding often involves conformational changes between two or more states, whereby different binding mechanisms are possible even with a simple two-state description. Two models are widely used to portray protein-ligand interactions: Induced fit and conformational selection. However, distinguishing them experimentally is challenging. Single-molecule Förster resonance energy transfer (smFRET) has emerged as a powerful tool to resolve structural dynamics at the level of single proteins. Here, we investigated immobilized Zika virus (ZIKV) and dengue virus (DENV2) NS2B-NS3 proteases using smFRET to compare their conformational changes upon binding to competitive small molecule inhibitors. The analysis of the smFRET data allowed us to distinguish between induced fit and conformational selection models and assign the binding mechanism from the kinetic parameters obtained. Although DENV and ZIKV protease are proteins with high structural similarities, our results reveal that they have opposite binding mechanisms for competitive ligands. While the protein-ligand interaction in the ZIKV protease follows an induced fit mechanism, the DENV protease follows the conformational selection mechanism.

Synthetic routes are reported for the three analogues of the simplest L-2-amino-dicarboxylic acids, aspartate, glutamate, and aminoadipate, in which the silanetriol group (Si(OH)₃) replaces the distal carboxyl group (CO₂H). Direct access to the silanetriol amino acids relied either on catalytic hydrosilylation of a terminal alkene using triethoxysilane, or on alkylation of a glycine equivalent anion by triallyl(iodomethyl)silane. In both cases, acid hydrolysis afforded the silanetriol amino acids. These were shown to self-assemble into siloxane Si-O clusters as their concentration in water increased in the pH range of 1–12. Such reversible cross-linking did not prevent silanetriol amino acids from serving as substrates of an aminotransferase enzyme, boding well for their utilization as microbial nutrients to encompass silicon in future stages of metabolism and polypeptide edifices.

In the energy landscape of coordination-driven self-assembly processes, the isolation of kinetically formed supramolecular cages has long been identified as a challenging task. This study reports a reliable strategy for the selective isolation of kinetically or thermodynamically preferred stable coordination cages, whose formation depends on the degree of steric protection offered by the exterior side chains. The combination of Pd^II ions with arc-shaped 2,2′-bianthryl-based ligands that contain different numbers of methoxyethoxy side chains led to the quantitative formation of both kinetically favorable monomeric M₂L₄ cages and thermodynamically favorable dimeric (M₂L₄)₂ interlocked cages. These assemblies were structurally fully characterized via NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analysis. Although the monomeric cages with fewer exterior side chains can reassemble into interlocked cages, the cages with more exterior substituents remain monomeric cages under similar conditions. A computational study revealed that this different behavior is mainly governed by the destabilization of the interlocking assemblies due to the steric repulsion among the side chains on the overcrowded exterior. Furthermore, the kinetically stabilized monomeric M₂L₄ cages exhibit permanent host abilities toward sulfonate guests, while the cages with lower steric protection undergo dimerization accompanied by guest release.

The chiroptical properties of a chiral N-doped nanographene have been modulated for the first time by means of redox and pH changes as external stimuli. A new absorption band appeared in the NIR region after the addition of an oxidant or an acid, forming the corresponding oxidized or protonated species. In their Research Article, Núria Crivillers, Araceli G. Campaña, Sara P. Morcillo, and co-workers consider that the multi-optical response switching for which the NIR band can be modulated by changing the pH and the redox state is a remarkable achievement for future applications based on this phenomenon.

The Front Cover depicts binding of several neutral, divalent Group 10 metal chelates by human serum albumin (HSA, teal coils) at multiple binding sites (purple space-filling models; Pd^II chelate species). The thermodynamics of spontaneous metal chelate/ligand uptake are governed by the identity of the metal ion. While the reactions are enthalpically driven, the entropy contribution becomes more favourable with increasing metal ion size. Importantly, the chelates do not demetallate upon uptake by HSA, as detailed by Sheldon Sookai and Orde Q. Munro in their Research Article.