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

Abstract

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.

Piperazine-Fused Cyclic Disulfides Unlock High-Performance Bioreductive Probes of Thioredoxins and Bifunctional Reagents for Thiol Redox Biology

“…To reach the diselenide targets 10T/C , we needed a different method of selenium introduction, as selenoesters are notoriously unstable; so, we treated the dimesylates 3T/C with KSeCN. To minimize exposure to Se species, we aimed to convert the bis-selenocyanate products to diselenanes 8 in a one-pot procedure.…”

Cyclic Dichalcogenides Extend the Reach of Bioreductive Prodrugs to Harness Thiol/Disulfide Oxidoreductases: Applications to seco-Duocarmycins Targeting the Thioredoxin System

“… Redox triggers for modular prodrugs. 1st generation Trx-triggers SS60 and solubilized P-SS60 ; 2nd generation solubilized bicyclic Trx-triggers Me-SS66T , Me-SS66C , and P-SS66C ; TrxR-trigger SeS60 . , “Upper limit” control triggers: very labile MC , monothiol-labile SS00 M . “Lower limit” control triggers: hydrolysis benchmarks O56 and P-CC60 , and carbamate stability test OBn .…”

“…19 Cyclic selenenyl sulfides instead had a selenium-preferring, regioisomer-dependent activation mechanism, making them excellently selective substrates for TrxR1 in live cells. 18,20 These bioreductive motifs were validated in fluorogenic probes in acute applications (minutes to hours) in cell culture. However, it is unknown whether such designs can be useful for long-term redox-selective drug delivery, particularly in the context of cancer, for which their Trx/ TrxR targets' biology is most relevant (Figure 1b) since in vivo uses are more stringent, e.g., requiring them to also resist activation by hydrolytic or oxidative metabolism in the long term.…”

“…Recently, we have developed sets of 6-membered cyclic dichalcogenides with unique reduction-resisting properties as well as reductase selectivity profiles. − Stabilized disulfides in these series were selectively activated by Trxs, with excellent resistance to even thousand-fold higher levels of GSH and monothiols, and bifunctional bicyclic disulfides permitted drastic enhancement of their reductive activation kinetics . Cyclic selenenyl sulfides instead had a selenium-preferring, regioisomer-dependent activation mechanism, making them excellently selective substrates for TrxR1 in live cells. , These bioreductive motifs were validated in fluorogenic probes in acute applications (minutes to hours) in cell culture. However, it is unknown whether such designs can be useful for long-term redox-selective drug delivery, particularly in the context of cancer, for which their Trx/TrxR targets’ biology is most relevant (Figure b) since in vivo uses are more stringent, e.g., requiring them to also resist activation by hydrolytic or oxidative metabolism in the long term.…”

Piperazine-fused cyclic disulfides: high-performance bioreduction-activated cores for bifunctional probes and reagents

“…Unsatisfied by the high step-count and time-cost of that route, we then tested direct olefin (di-)amination, as pioneered by Sharpless and recently refined by Okumura To introduce seleniums, we avoided taking an analogous route to that for sulfur since selenoesters are notoriously unstable 17 . Selenium could be instead introduced to dimesylates 3T/C using KSeCN.…”