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- Title
Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation.
- Authors
Reuter, Cédric; Opitz, Robert; Soicke, Arne; Dohmen, Stephan; Barone, Matthias; Chiha, Slim; Klein, Marco Tobias; Neudörfl, Jörg ‐ Martin; Kühne, Ronald; Schmalz, Hans ‐ Günther
- Abstract
With the aim of developing polyproline type II helix (PPII) secondary-structure mimetics for the modulation of prolin-rich-mediated protein-protein interactions, the novel diproline mimetic ProM-2 was designed by bridging the two pyrrolidine rings of a diproline (Pro-Pro) unit through a Z-vinylidene moiety. This scaffold, which closely resembles a section of a PPII helix, was then stereoselectively synthesized by exploiting a ruthenium-catalyzed ring-closing metathesis (RCM) as a late key step. The required vinylproline building blocks, that is, ( R)- N-Boc-2-vinylproline (Boc= tert-butyloxycarbonyl) and ( S,S)-5-vinylproline- tert-butyl ester, were prepared on a gram scale as pure stereoisomers. The difficult peptide coupling of the sterically demanding building blocks was achieved in good yield and without epimerization by using 2-(1 H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/ N, N-diisopropylethylamine (DIPEA). The RCM proceeded smoothly in the presence of the Grubbs II catalyst. Stereostructural assignments for several intermediates were secured by X-ray crystallography. As a proof of concept, it was shown that certain peptides containing ProM-2 exhibited improved (canonical) binding towards the Ena/VASP homology 1 (EVH1) domain as a relevant protein interaction target.
- Subjects
POLYPROLINE; PROTEIN-protein interactions; INTERMOLECULAR interactions; PROTEIN-ligand interactions; PYRROLIDINE; VINYLIDENE compounds; STEREOISOMERS; RUTHENIUM
- Publication
Chemistry - A European Journal, 2015, Vol 21, Issue 23, p8464
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201406493