Carba-Sugar Derivatives of Glucosamine-6-Phosphate as Novel Activators for the Glms-Riboswitch

PS1 Poster session 1 Odd numbers
Location (hall): 
Start/end time: 
Monday, July 1, 2019 - 15:45 to 17:15

David Stängle1, Paul Gehle2, Anna Schüller2, Günter Mayer2, Valentin Wittmann1

1University of Konstanz, Konstanz, Germany, 2University of Bonn, Bonn, Germany

The glmS-riboswitch is a new target to fight multi-resistant bacterial strains. This RNA segment is encoding for the glucosamine-6-phosphate synthase (GlmS) that is essential for the formation of glucosamine-6-phosphate (GlcN6P), an important building block in the early steps of the bacterial cell wall biosynthesis [1]. At elevated concentrations, GlcN6P can bind to the aptamer region of the glmS-riboswitch and induce a self-cleavage reaction. Eventually, the RNA segment is degraded and the formation of GlmS is stopped. 

Previously, we could show that carba-sugar derivatives of GlcN6P are able to bind to the glmS-riboswitch and induce the self-cleavage reaction [2]. Here, we present the synthesis of novel carba-sugar derivatives 7 of GlcN6P that are substituted at the carba position (Scheme 1). The key steps of this synthesis route are a ring-closing metathesis (RCM) reaction (3 → 4) and a hydroboration (4 → 5) that results in key intermediate 5. Further derivatization by alkylation and phosphorylation yields 7. The activity of the synthesized compounds in the self-cleavage reaction of the glmS-riboswitch, as evaluated by biological in-vitro self-cleavage assays, is presented.

Scheme 1: Synthesis of derivatives 7 of (5aS)-carba-glucosamine-6-phosphate. Commercially available GlcNAc 1 was converted into diol 2 and further into diene 3. 3 was applied to an RCM reaction to give cyclic olefine 4. Subsequent benzylation and hydroboration led to the key intermediate 5 which was derivatized to produce derivatives 6 of (5aS)-carba-glucosamine. Finally, a regioselective phosphorylation at the C-6 hydroxy group yielded 7.

  1. Breaker, Ronald R., Prospects for Riboswitch Discovery and Analysis. Mol. Cell 2011, 43 (6), 867-879.
  2. a) Lünse, C. E.; Schmidt, M. S.; Wittmann, V.; Mayer, G., Carba-sugars Activate the glmS-Riboswitch of Staphylococcus aureus. ACS Chem. Biol. 2011, 6 (7), 675-678.; b) Schüller, A.; Matzner, D.; Lünse, C. E.; Wittmann, V.; Schumacher, C.; Unsleber, S.; Brötz-Oesterhelt, H.; Mayer, C.; Bierbaum, G.; Mayer, G., Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition. ChemBioChem 2017, 18 (5), 435-440.; c) Matzner, D.; Schüller, A.; Seitz, T.; Wittmann, V.; Mayer, G., Fluoro-Carba-Sugars are Glycomimetic Activators of the glmS Ribozyme. Chem. Eur. J. 2017, 23 (51), 12604-12612.