Thiol-reactive inhibitors for the cellular entry of cyclic oligochalcogenide (COC) transporters and SARS-CoV-2 spike pseudo-lentivirus are reported.

The development of facile methods for screening organic functional molecules through C-H bond activation is a revolutionary trend in materials research. The prediction of mechanochromism as well as mechanochromic trends of luminogens is an appealing yet challenging puzzle. Here, we present a strategy for the design of mechanochromic luminogens based on the dipole moment of donor-acceptor molecules. For this purpose, a highly efficient route to 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines (2,7-diaryl-TAPs) has been established through programmed C-H arylation, which unlocks a great opportunity to rapidly assemble a library of fluorophores for the discovery of mechanochromic regularity. Molecular dipole moment can be employed to explain and further predict the mechanochromic trends. The 2,7-diaryl-TAPs with electron-donating groups on the 2-aryl and electron-withdrawing groups on the 7-aryl possess a relatively small dipole moment and exhibit a red-shifted mechanochromism. When the two aryls are interchanged, the resulting luminogens have a relatively large dipole moment and display a blue-shifted mechanochromism. Seven pairs of isomers with opposite mechanochromic trends are presented as illustrative examples. The aryl-interchanged congeners with a bidirectional emission shift are structurally similar, which provides an avenue for understanding in-depth the mechanochromic mechanism.

The development of straightforward accesses to organic functional materials through C-H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor-acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C-H/C-H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm(-1) in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostability. Indazo-Fluor 5h exhibits superior photostability and very low cytotoxicity, which would be a prominent reagent for in vivo mitochondria imaging.

Cyclic oligochalcogenides (COCs) are emerging as promising systems to penetrate cells. Clearly better than and different to the reported diselenolanes and epidithiodiketopiperazines, we introduce the benzopolysulfanes (BPS), which show efficient delivery, insensitivity to inhibitors of endocytosis, and compatibility with substrates as large as proteins. This high activity coincides with high reactivity, selectively toward thiols, exceeding exchange rates of disulfides under tension. The result is a dynamic‐covalent network of extreme sulfur species, including cyclic oligomers, from dimers to heptamers, with up to nineteen sulfurs in the ring. Selection from this unfolding adaptive network then yields the reactivities and selectivities needed to access new uptake pathways. Contrary to other COCs, BPS show high retention on thiol affinity columns. The identification of new modes of cell penetration is important because they promise new solutions to challenges in delivery and beyond.

The purpose of this article is to give a brief review of weak chelation-assistance as a powerful means for the rhodium-catalyzed annulation of arenes with alkynes. The use of commonly occurring functional groups (e.g., ketones, aldehydes, carboxylic acids and alcohols) as the directing groups enriches the versatility of auxiliary ligands and extends the scope of products. This short article offers an overview on emerging procedures, highlights their advantages and limitations, and covers the latest progress in the rapid synthesis of organic functional materials and natural products.

In this report, cell-penetrating streptavidin (CPS) is introduced to exploit the full power of streptavidin−biotin biotechnology in cellular uptake. For this purpose, transporters, here cyclic oligochalcogenides (COCs), are covalently attached to lysines of wild-type streptavidin. This leaves all four biotin binding sites free for at least bifunctional delivery. To maximize the standards of the quantitative evaluation of cytosolic delivery, the recent chloroalkane penetration assay (CAPA) is coupled with automated high content (HC) imaging, a technique that combines the advantages of fluorescence microscopy and flow cytometry. According to the resulting HC-CAPA, cytosolic delivery of CPS equipped with four benzopolysulfanes was the best among all tested CPSs, also better than the much smaller TAT peptide, the original cell-penetrating peptide from HIV. HaloTag-GFP fusion proteins expressed on mitochondria were successfully targeted using CPS carrying two different biotinylated ligands, HaloTag substrates or anti-GFP nanobodies, interfaced with peptide nucleic acids, flipper force probes, or fluorescent substrates. The delivered substrates could be released from CPS into the cytosol through desthiobiotin−biotin exchange. These results validate CPS as a general tool which enables unrestricted use of streptavidin−biotin biotechnology in cellular uptake.

Spatiotemporal prediction is challenging due to the complex dynamic motion and appearance changes. Existing work concentrates on embedding additional cells into the standard ConvLSTM to memorize spatial appearances during the prediction. These models always rely on the convolution layers to capture the spatial dependence, which are local and inefficient. However, long-range spatial dependencies are significant for spatial applications. To extract spatial features with both global and local dependencies, we introduce the self-attention mechanism into ConvLSTM. Specifically, a novel self-attention memory (SAM) is proposed to memorize features with long-range dependencies in terms of spatial and temporal domains. Based on the self-attention, SAM can produce features by aggregating features across all positions of both the input itself and memory features with pair-wise similarity scores. Moreover, the additional memory is updated by a gating mechanism on aggregated features and an established highway with the memory of the previous time step. Therefore, through SAM, we can extract features with long-range spatiotemporal dependencies. Furthermore, we embed the SAM into a standard ConvLSTM to construct a self-attention ConvLSTM (SA-ConvLSTM) for the spatiotemporal prediction. In experiments, we apply the SA-ConvLSTM to perform frame prediction on the MovingMNIST and KTH datasets and traffic flow prediction on the TexiBJ dataset. Our SA-ConvLSTM achieves state-of-the-art results on both datasets with fewer parameters and higher time efficiency than previous state-of-the-art method.

Thiol-mediated uptake is emerging as a powerful method to penetrate cells. Cyclic oligochalcogenides (COCs) have been identified as privileged scaffolds to enable and inhibit thiol-mediated uptake because they can act as dynamic covalent cascade exchangers, i.e., every exchange produces a new, covalently tethered exchanger. In this study, our focus is on the essentially unexplored COCs of higher oxidation levels. Quantitative characterization of the underlying dynamic covalent exchange cascades reveals that the initial ring opening of cyclic thiosulfonates (CTOs) proceeds at a high speed even at a low pH. The released sulfinates exchange with disulfides in aprotic but much less in protic environments. Hydrophobic domains were thus introduced to direct CTOs into hydrophobic pockets to enhance their reactivity. Equipped with such directing groups, fluorescently labeled CTOs entered the cytosol of living cells more efficiently than the popular asparagusic acid. Added as competitive agents, CTOs inhibit the uptake of various COC transporters and SARS-CoV-2 lentivectors. Orthogonal trends found with different transporters support the existence of multiple cellular partners to account for the diverse expressions of thiol-mediated uptake. Dominant self-inhibition and high activity of dimers imply selective and synergistic exchange in hydrophobic pockets as distinguishing characteristics of thiol-mediated uptake with CTOs. The best CTO dimers with hydrophobic directing groups inhibit the cellular entry of SARS-CoV-2 lentivectors with an IC 50 significantly lower than the previous best CTO, below the 10 μM threshold and better than ebselen. Taken together, these results identify CTOs as an intriguing motif for use in cytosolic delivery, as inhibitors of lentivector entry, and for the evolution of dynamic covalent networks in the broadest sense, with reactivity-based selectivity of cascade exchange emerging as a distinguishing characteristic that deserves further attention.