Development and biological applications of sulfur–triazole exchange (SuTEx) chemistry

Abstract

This review discusses the development of sulfonyl–triazoles and highlights the merits and opportunities for deploying this sulfur electrophile for biological discovery.

Discovery of a Cell‐Active SuTEx Ligand of Prostaglandin Reductase 2

“…Sulfonyl‐triazoles represent a promising scaffold for developing global tyrosine‐reactive probes and protein‐targeted ligands [19] . With the exception of an in situ active GSTP1 inhibitor, previous efforts using SuTEx fragment compounds have been concentrated largely to evaluation of activity in cell lysates.…”

Reactive chemistry for covalent probe and therapeutic development

“…As described in the previous section, SuFEx molecules have been shown to react with tyrosine sites on proteins [93,95]. Our group recently introduced sulfonyl triazoles as a new reactive group for preferential modification of tyrosines in catalytic and noncatalytic sites of proteins through sulfur-triazole exchange (SuTEx) chemistry (Figure 5D) [103]. SuTEx shares common features with SuFEx.…”

“…The deployment of a heterocyclic LG, however, offers an additional site for functional group modifications that enables covalent probe development. A dramatic increase in reactivity was observed for sulfonyl probes containing a triazolide compared with a fluoride LG, which could be due to additional stabilization from resonance in the former LG [103]. The enhanced reactivity facilitated development of first-generation SuTEx probes that were stable in aqueous solvents and could broadly modify thousands of tyrosine sites in lysates and live cells.…”

Cereblon covalent modulation through structure-based design of histidine targeting chemical probes

“…A variation of the SuFEx strategy called sulfur-triazole exchange (SuTEx) chemistry was recently reported where the fluorine is replaced by triazole heteroaromatic rings that enable further tuning of the leaving group to modulate reactivity and specificity. [19][20][21] Promiscuous SuTEx probes were shown to chemoselectively target tyrosine residues in proteomics experiments, whilst the labelling of histidine was negligible. We hypothesized that sulfonyl-exchange chemistry could be a broadly applicable platform for the specific targeting of histidine residues in proteins through the rational design of chemical probes with optimal equilibrium binding interactions.…”