title: Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation.
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-(1H-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.
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany).
authors.forename: Cédric
authors.initials: C
authors.lastname: Reuter
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany).
authors.forename: Robert
authors.initials: R
authors.lastname: Opitz
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany).
authors.forename: Arne
authors.initials: A
authors.lastname: Soicke
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany).
authors.forename: Stephan
authors.initials: S
authors.lastname: Dohmen
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany).
authors.forename: Matthias
authors.initials: M
authors.lastname: Barone
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany).
authors.forename: Slim
authors.initials: S
authors.lastname: Chiha
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany).
authors.forename: Marco Tobias
authors.initials: MT
authors.lastname: Klein
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany).
authors.forename: Jörg-Martin
authors.initials: JM
authors.lastname: Neudörfl
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany). kuehne@fmp-berlin.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Kühne
authors.affiliation: Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany). schmalz@uni-koeln.de.
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Schmalz
mesh_terms: D004151:Dipeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D057786:Peptidomimetics; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D004151:Dipeptides; D010455:Peptides; D057786:Peptidomimetics; D011506:Proteins; C448039:prolyl-proline; C011083:polyproline
keywords: amino acids; conformation analysis; helical structures; peptidomimetics; protein-protein interactions