Asparagusic Golgi Trackers.

Thiol-mediated uptake (TMU) is thought to occur through dynamic covalent cascade exchange networks. Here we show that the cascade accounting for TMU of asparagusic acid derivatives (AspA) ends in the Golgi apparatus (G) and shifts from disulfide to thioester exchange with palmitoyl transferases as the final exchange partner. As a result, AspA combined with pH-sensitive fluoresceins, red-shifted silicon-rhodamines, or mechanosensitive flipper probes selectively labels the Golgi apparatus in fluorescence microscopy images in living and fixed cells.

Thiol-Mediated Uptake (TMU, TIMEUP).

This account briefly summarizes objectives and progress made so far with the Swiss-ERC AdG entitled Translational Dynamic Covalent Exchange Cascades (TIMEUP).

Electric-Field Catalysis on Carbon Nanotubes in Electromicrofluidic Reactors: Monoterpene Cyclizations.

The control over the movement of electrons during chemical reactions with oriented external electric fields (OEEFs) has been predicted to offer a general approach to catalysis. Recently, we suggested that many problems to realize electric-field catalysis in practice under scalable bulk conditions could possibly be solved on multiwalled carbon nanotubes in electromicrofluidic reactors. Here, we selected monoterpene cyclizations to assess the scope of our system in organic synthesis.

Tutorial: fluorescence lifetime microscopy of membrane mechanosensitive Flipper probes.

Measuring forces within living cells remains a technical challenge. In this Tutorial, we cover the development of hydrophobic mechanosensing fluorescent probes called Flippers, whose fluorescence lifetime depends on lipid packing. Flipper probes can therefore be used as reporters for membrane tension via the measurement of changes in their fluorescence lifetime.

Single-Molecule Localization Microscopy and Tracking with a Fluorescent Mechanosensitive Probe.

A milestone in optical imaging of mechanical forces in cells has been the development of the family of flipper fluorescent probes able to report membrane tension noninvasively in living cells through their fluorescence lifetime. The specifically designed Flipper-CF probe with an engineered inherent blinking mechanism was recently introduced for super-resolution fluorescence microscopy of lipid ordered membranes but was too dim to be detected in lipid disordered membranes at the single-molecule level (García-Calvo, J. 2020, 142(28), 12034-12038).

Excitation-Wavelength-Dependent Photophysics of a Torsionally Disordered Push-Pull Dye.

The torsional disorder of conjugated dyes in the electronic ground state can lead to inhomogeneous broadening of the S ←S absorption band, allowing for the selective photoexcitation of molecules with different amounts of distortion. Here, we investigate how this affects electronic transitions to upper excited states. We show that torsion of a core-alkynylated push-pull dye can have opposite effects on the oscillator strength of its lowest-energy transitions.

Pnictogen-Bonding Enzymes.

The objective of this study was to create artificial enzymes that capitalize on pnictogen bonding, a σ-hole interaction that is essentially absent in biocatalysis. For this purpose, stibine catalysts were equipped with a biotin derivative and combined with streptavidin mutants to identify an efficient transfer hydrogenation catalyst for the reduction of a fluorogenic quinoline substrate. Increased catalytic activity from wild-type streptavidin to the best mutants coincides with the depth of the σ hole on the Sb(V) center, and the emergence of saturation kinetic behavior.

Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake.

Thiol-mediated uptake (TMU) is an intriguing enigma in current chemistry and biology. While the appearance of cell-penetrating activity upon attachment of cascade exchangers (CAXs) has been observed by many and is increasingly being used in practice, the molecular basis of TMU is essentially unknown. The objective of this study was to develop a general protocol to decode the dynamic covalent networks that presumably account for TMU.

Core-Alkynylated Fluorescent Flippers: Altered Ultrafast Photophysics to Track Thick Membranes.

Fluorescent flippers have been introduced as small-molecule probes to image membrane tension in living systems. This study describes the design, synthesis, spectroscopic and imaging properties of flippers that are elongated by one and two alkynes inserted between the push and the pull dithienothiophene domains. The resulting mechanophores combine characteristics of flippers, reporting on physical compression in the ground state, and molecular rotors, reporting on torsional motion in the excited state, to take their photophysics to new level of sophistication.

Subphthalocyanine-flipper dyads for selective membrane staining.

The design, synthesis and evaluation of a subphthalocyanine-flipper (SubPc-Flipper) amphiphilic dyad is reported. This dyad combines two fluorophores that function in the visible region (420-800 nm) for the simultaneous sensing of both ordered and disordered lipidic membranes. The flipper probes part of the dyad possesses mechanosensitivity, long fluorescence lifetimes ( = 3.

Anion-π catalysis on carbon allotropes.

Anion-π catalysis, introduced in 2013, stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion-π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion-π interactions. With these expectations, anion-π catalysis on fullerenes has been introduced in 2017, followed by carbon nanotubes in 2019.

Dynamic Phosphorus: Thiolate Exchange Cascades with Higher Phosphorothioates.

In this study, we introduce phosphorus, a pnictogen, as an exchange center for dynamic covalent chemistry. Cascade exchange of neutral phosphorotri- and -tetrathioates with thiolates is demonstrated in organic solvents, aqueous micellar systems, and in living cells. Exchange rates increase with the pH value, electrophilicity of the exchange center, and nucleophilicity of the exchangers.

Electric field-assisted anion-π catalysis on carbon nanotubes in electrochemical microfluidic devices.

The vision to control the charges migrating during reactions with external electric fields is attractive because of the promise of general catalysis, emergent properties, and programmable devices. Here, we explore this idea with anion-π catalysis, that is the stabilization of anionic transition states on aromatic surfaces. Catalyst activation by polarization of the aromatic system is most effective.

Fluorogenic Thioacetalization: Expanding the Chemical Space of Fluorescent Probes, Including Unorthodox, Bifurcated, and Mechanosensitive Chalcogen Bonds.

Progress with fluorescent flippers, small-molecule probes to image membrane tension in living systems, has been limited by the effort needed to synthesize the twisted push-pull mechanophore. Here, we move to a higher oxidation level to introduce a new design paradigm that allows the screening of flipper probes rapidly, at best . Late-stage clicking of thioacetals and acetals allows simultaneous attachment of targeting units and interfacers and exploration of the critical chalcogen-bonding donor at the same time.

Anion-(π) -π Catalytic Micelles.

Anion-π catalysis operates by stabilizing anionic transition states on π-acidic aromatic surfaces. In anion-(π) -π catalysis, π stacks add polarizability to strengthen interactions. In search of synthetic methods to extend π stacks beyond the limits of foldamers, the self-assembly of micelles from amphiphilic naphthalenediimides (NDIs) is introduced.

The Origin of Anion-π Autocatalysis.

The autocatalysis of epoxide-opening ether cyclizations on the aromatic surface of anion-π catalysts stands out as a leading example of emergent properties expected from the integration of unorthodox interactions into catalysis. A working hypothesis was proposed early on, but the mechanism of anion-π autocatalysis has never been elucidated. Here, we show that anion-π autocatalysis is almost independent of peripheral crowding in substrate and product.

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake.

Integrins are cell surface proteins responsible for cell motility. Inspired by the rich disulfide exchange chemistry of integrins, we show here the inhibition of cell migration by cascade exchangers (CAXs), which also enable and inhibit cell penetration by thiol-mediated uptake. Fast-moving CAXs such as reversible Michael acceptor dimers, dithiabismepanes, and bioinspired epidithiodiketopiperazines are best, much better than Ellman's reagent.

Fluorescent Flippers: Small-Molecule Probes to Image Membrane Tension in Living Systems.

Flipper probes have been introduced as small molecule fluorophores to image physical forces, that is, membrane tension in living systems. Their emergence over one decade is described, from evolution in design and synthesis to spectroscopic properties. Responsiveness to physical compression in equilibrium at the ground state is identified as the ideal origin of mechanosensitivity to image membrane tension in living cells.

Correction: Tyrosine bioconjugation with hypervalent iodine.

[This corrects the article DOI: 10.1039/D2SC04558C.].

Tyrosine bioconjugation with hypervalent iodine.

Hypervalent iodine reagents have recently emerged as powerful tools for late-stage peptide and protein functionalization. Herein we report a tyrosine bioconjugation methodology for the introduction of hypervalent iodine onto biomolecules under physiological conditions. Tyrosine residues were engaged in a selective addition onto the alkynyl bond of ethynylbenziodoxolones (EBX), resulting in stable vinylbenziodoxolones (VBX) bioconjugates.

Decoded fingerprints of hyperresponsive, expanding product space: polyether cascade cyclizations as tools to elucidate supramolecular catalysis.

Simple enough to be understood and complex enough to be revealing, cascade cyclizations of diepoxides are introduced as new tools to characterize supramolecular catalysis. Decoded product fingerprints are provided for a consistent set of substrate stereoisomers, and shown to report on chemo-, diastereo- and enantioselectivity, mechanism and even autocatalysis. Application of the new tool to representative supramolecular systems reveals, for instance, that pnictogen-bonding catalysis is not only best in breaking the Baldwin rules but also converts substrate diastereomers into completely different products.

Dynamic Covalent Michael Acceptors to Penetrate Cells: Thiol-Mediated Uptake with Tetrel-Centered Exchange Cascades, Assisted by Halogen-Bonding Switches.

Chalcogen-centered cascade exchange chemistry is increasingly understood to account for thiol-mediated uptake, that is, the ability of reversibly thiol-reactive agents to penetrate cells. Here, reversible Michael acceptors are shown to enable and inhibit thiol-mediated uptake, including the cytosolic delivery of proteins. Dynamic cyano-cinnamate dimers rival the best chalcogen-centered inhibitors.

Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry.

Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mostly cyclic oligochalcogenides, particularly disulfides. The objective of this study was to expand the dynamic covalent chalcogen exchange cascades in thiol-mediated uptake by inserting pnictogen relays.

Cyclic Thiosulfonates for Thiol-Mediated Uptake: Cascade Exchangers, Transporters, Inhibitors.

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.

The Dynamic Range of Acidity: Tracking Rules for the Unidirectional Penetration of Cellular Compartments.

Labeled ammonium cations with pK ∼7.4 accumulate in acidic organelles because they can be neutralized transiently to cross the membrane at cytosolic pH 7.2 but not at their internal pH<5.