ISPAAC: Isomer‐Free Generation of a Bcl‐xL‐Inhibitor in Living Cells. Issue 52 (20th August 2018)

• Record Type: Journal Article
• Authors: Lis, Christian; Rubner, Stefan; Gröst, Corinna; Hoffmann, Ralf; Knappe, Daniel; Berg, Thorsten
• Is Part Of: Chemistry. Volume 24:Issue 52(2018)
• Page Start: 13762
• Page End: 13766
• Publication Date: 2018-08-20
• Subjects: apoptosis -- bioorthogonal chemistry -- cyclooctynes -- inhibitors -- protein–protein interactions; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201803032
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Strain‐promoted azide–alkyne cycloadditions (SPAAC) have proven extremely useful for labeling of biomolecules, but typically produce isomeric mixtures. This is not appropriate for the formation of bioactive molecules in living cells. Here, the first use of SPAAC for the isomer‐free synthesis of a bioactive molecule is reported both in vitro and inside cultured cells. We developed the symmetrical cyclooctyne SYPCO and used it for the generation of a chemically uniform triazole inhibitor of protein–protein interactions mediated by Bcl‐xL via isomer‐free SPAAC (iSPAAC). Tumor cells treated with the reactants of the iSPAAC reaction contained higher concentrations of triazole, and displayed higher apoptosis levels, than cells treated with pre‐synthesized triazole. We envision iSPAAC as a broadly applicable method for modulating intracellular targets with organic molecules with molecular weights prohibitively large for cellular uptake, via smaller and thus more cell‐permeable components. Abstract : Isomer‐free zone : The formation of isomers in strain‐promoted azide–alkyne cycloadditions (SPAAC) has precluded their use for the formation of bioactive molecules in living cells. Here, the first isomer‐free generation of a bioactive molecule by SPAAC is presented. The cycloalkyne SYPCO (sy mmetricalp yrroloc ycloo ctyne) facilitated the intracellular synthesis of a rationally designed inhibitor of protein–protein interactions mediated by Bcl‐xL via isomer‐free SPAAC (iSPAAC).