Dynamic Covalent Chemistry as a Facile Route to Unusual Main‐Group Thiolate Assemblies and Disulfide Hoops and Cages

Phan, Ngoc-Minh; Percástegui, Edmundo G.; Johnson, Darren W.

doi:10.1002/cplu.202000257

Cited by 21 publications

(27 citation statements)

References 63 publications

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“…Dynamic covalent sulfur exchange cascades before or during direct translocation across the plasma membrane into the cytosol appear to dominate with synthetic delivery systems. , HIV entry is an established example for inhibitable dynamic covalent sulfur exchange on cell surfaces followed by membrane fusion, while dynamic covalent sulfur exchange with proteases in endosomes and lysosomes, such as cathepsins, can, perhaps, be considered as arguably borderline examples for thiol-mediated uptake combined with endocytosis . More precise mechanistic information is often missing, particularly for direct translocation, also because dynamic covalent chemistry − dramatically complicates, and discourages, target identification. However, it is also this dynamic covalent chemistry that makes thiol-mediated uptake so unique and attractive, particularly from the viewpoint of supramolecular chemistry.…”

Section: Introductionmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

110

208

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This Perspective focuses on thiol-mediated uptake, that is, the entry of substrates into cells enabled by oligochalcogenides or mimics, often disulfides, and inhibited by thiol-reactive agents. A short chronology from the initial observations in 1990 until today is followed by a summary of cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs) as privileged scaffolds in thiol-mediated uptake and inhibitors of thiol-mediated uptake as potential antivirals. In the spirit of a Perspective, the main part brings together topics that possibly could help to explain how thiol-mediated uptake really works. Extreme sulfur chemistry mostly related to COCs and their mimics, cyclic disulfides, thiosulfinates/-onates, diselenolanes, benzopolysulfanes, but also arsenics and Michael acceptors, is viewed in the context of acidity, ring tension, exchange cascades, adaptive networks, exchange affinity columns, molecular walkers, ring-opening polymerizations, and templated polymerizations. Micellar pores (or lipid ion channels) are considered, from cell-penetrating peptides and natural antibiotics to voltage sensors, and a concise gallery of membrane proteins, as possible targets of thiol-mediated uptake, is provided, including CLIC1, a thiol-reactive chloride channel; TMEM16F, a Ca-activated scramblase; EGFR, the epithelial growth factor receptor; and protein-disulfide isomerase, known from HIV entry or the transferrin receptor, a top hit in proteomics and recently identified in the cellular entry of SARS-CoV-2.

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Section: Introductionmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

110

208

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“…The family of biphenyl disulphides is important due to their applications as drugs, [15] sensors, [16] lubricants, [17] polymers; [18–21] source of PhS substituents in organic reactions [22, 23] and precursors for supramolecular systems [24–26] . Recently we showed that di‐ p ‐tolyl disulphide (4‐CH 3 ‐PhS) 2 absorbs the energy of compression by phase transitions and conformational transformations [27] .…”

Section: Polymorph α[31] β γmentioning

confidence: 99%

High‐pressure Nucleation of Low‐Density Polymorphs**

Sobczak

Ratajczyk

Katrusiak

2021

Chemistry A European J

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New polymorphs b and g of bis-3-nitrophenyl disulphide, crystallized above 0.3 GPa, are less dense than the ambient-pressure polymorph a.T his counterintuitive density relationr esults from the high-entropy nucleation and subsequent kinetic crystallization. The work performed by pressure compensates the high entropy and temperature product, substantiated in varied conformers and increasedc hemical potential. Pressure-increased viscosity promotes the kinetic polymorphs, in accordance with empirical Ostwald's rule of stages. It contrasts to mechanochemicalt echniques, favouring high-density polymorphs.The rational control over polymorphicf orms of organic compounds is one of the challenges of materials sciences, modern chemistry,and relatedtechnologies. [1][2][3] Apart from the environment (solvent, pressure,t emperature, composition, evaporation rate, etc.) also the intrinsic features (intra-and intermolecular interactions of conformers, mesmeric forms, tautomers, solvates etc.) need to be taken into account for designing the robust process aimed at the desired specific polymorph. [2,[4][5][6] Such precise technologiesa re appliedf or obtaining required forms of pharmaceuticals, pesticides, food, plastics, dyes and variouso ther products.D espite ac onsiderable progress in the crystal-structure prediction, [7][8][9][10] in most cases the experimental screening provides the most reliable information about polymorphso fc ompounds. Generally,t he crystal form resultsf rom the initial aggregation of molecules, either primary or secondary nucleation, and from the time-dependent crystal growth, either dynamic or kinetic. [1,2,5,11] The dynamic crystallizations proceeds lowly,i nt he nearly equilibrated systems, whereas the kineticc rystallizations take place off the thermodynamic equi-[a] S.

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“…Pioneering work by Johnson and co-workers confirmed operational thiol/ate exchange on arsenic, antimony, and bismuth relays in dynamic covalent macrocyclic architectures. 32 , 33 In chemical biology, FlAsH probes 34 , 35 and molecular walkers exchanging along thiol tracks 36 are among the highlights. With regard to cellular uptake, facilitated, glutathione (GSH)-dependent penetration of bismuth has been proposed.…”

Section: Introductionmentioning

confidence: 99%

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

Lim

Kato

Besnard

et al. 2022

JACS Au

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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. A family of pnictogen-expanded cyclic disulfides covering As(III), Sb(III), and Bi(III) is introduced. Their ability to inhibit thiol-mediated cytosolic delivery is explored with fluorescently labeled CAXs as transporters. The promise of inhibiting viral entry is assessed with SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings are identified as privileged scaffolds. The same holds for six-membered 1,3,2-dithiarsinane rings made from asparagusic acid and para -aminophenylarsine oxide, which are inactive or toxic when used alone. These chemically complementary Bi(III) and As(III) cascade exchangers inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector uptake at concentrations of 10 μM or lower. Crystal structures, computational models, and exchange kinetics support that lentivector entry inhibition of the contracted dithiarsinane and the expanded dithiabismepane rings coincides with exchange cascades that occur without the release of the pnictogen relay and benefit from noncovalent pnictogen bonds. The identified leads open perspectives regarding drug delivery as well as unorthodox approaches toward dynamic covalent inhibition of cellular entry.

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Dynamic Covalent Chemistry as a Facile Route to Unusual Main‐Group Thiolate Assemblies and Disulfide Hoops and Cages

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.

Cited by 21 publications

References 63 publications

Thiol-Mediated Uptake

Thiol-Mediated Uptake

High‐pressure Nucleation of Low‐Density Polymorphs**

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

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