Regioselective, efficient and scalable syntheses of 1,2-thiaselenanes

Zeisel, Lukas; Maier, Martin S.; Thorn‐Seshold, Oliver

doi:10.26434/chemrxiv-2022-99slz

Cited by 2 publications

(3 citation statements)

References 15 publications

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“…with iodoacetamide probe 16, with the reaction in aqueous buffer at pH 7.4, giving full conversion to GS-SS66C-MF (17) within minutes (Fig 7b). In line with the monothiol-stability we established earlier for the SS66C, this establishes another synthetic modality which the dithiane-core is robust to.…”

Section: Gs-ss66c-mfmentioning

confidence: 99%

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Bifunctional, piperazine-fused cyclic disulfides for oxidoreductase-activated cellular proagents

Zeisel

Felber

Scholzen

et al. 2023

Preprint

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We report piperazine-fused six-membered-cyclic dichalcogenides as rapid-response redox sensors for probes, prodrugs, and bifunctional conjugates that interface with cellular thiol/disulfide redox biology. By combining the thermodynamic stability of 1,2-dithianes with unprecedently rapid kinetics of self-immolation after reduction, these motifs are uniquely reliable and flexible reduction-based sensors for live cell applications. We synthesise four cis- and trans-piperazine-fused cyclic disulfides and diselenides by scalable, diastereomerically pure, six-step synthetic routes with just one chromatographic purification. Fluorogenic probes using these redox-active diamines are >100-fold faster activated than the previously known monoamines, which now allowed us to deconvolute the kinetics of the reduction and the cyclisation steps during activation. The diastereomers have remarkably different reductant specificity. In particular, the cis-fused disulfides are only activated by strong vicinal dithiol reductants, while trans-fused disulfides are activated even by monothiols like GSH. Thus, although both disulfides are good substrates for glutaredoxins and thioredoxins in cell-free assays, upon cellular applications the cis-disulfide probes substantially report on oxidoreductase activity in the thioredoxin system (the trans-disulfides remain promiscuously reactive). Finally, we showcase efficient late-stage synthetic diversification of the piperazine-disulfides, promising their broad applicability as cleavable bifunctional cores for redox probes and prodrugs, for solid phase synthesis, and as linkers for antibody-drug conjugates.

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Section: Gs-ss66c-mfmentioning

confidence: 99%

“…For the selenium introduction, we avoided taking an analogous route to that for sulfur since selenoesters are notoriously unstable 17 . Se could be instead introduced to dimesylates 3T/C by KSeCN.…”

Section: Syntheses Of Dichalcogenide Piperazine Redox Substratesmentioning

confidence: 99%

Bifunctional, piperazine-fused cyclic disulfides for oxidoreductase-activated cellular proagents

Zeisel

Felber

Scholzen

et al. 2023

Preprint

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“…We focused on cost-and time-efficiency: using cheap commercially available reagents, minimising chromatographic purifications, and reducing the step count. 17,18 The straightforward syntheses we now provide address the growing need for functionalisable selenenyl sulfides in chemical biology and will also fill gaps in organochalcogen chemistry.…”

Section: Special Topic Synthesismentioning

confidence: 99%

Efficient and Scalable Syntheses of 1,2-Thiaselenane-4-amine and 1,2-Thiaselenane-5-amine

Zeisel¹,

Maier²,

Thorn‐Seshold³

2023

Synthesis

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We develop the first regioselective syntheses of 1,2-thiaselenane-4-amine (TSA4) and 1,2-thiaselenane-5-amine (TSA5): redox-active motifs with high value in chemical biology, that until now were hindered by tedious synthesis. We leverage an aziridine intermediate and a kinetically controlled S-acylation for regioselective chalcogen installations. We optimise short, fast sequences with just one or two chromatographic steps that cheaply deliver these motifs on scale for high-throughput inhibitor screening, and provide a robust methodology for assembling other selenenylsulfides.

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Regioselective, efficient and scalable syntheses of 1,2-thiaselenanes

Cited by 2 publications

References 15 publications

Bifunctional, piperazine-fused cyclic disulfides for oxidoreductase-activated cellular proagents

Bifunctional, piperazine-fused cyclic disulfides for oxidoreductase-activated cellular proagents

Efficient and Scalable Syntheses of 1,2-Thiaselenane-4-amine and 1,2-Thiaselenane-5-amine

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