Design and Stereoselective Synthesis of ProM‐2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation |
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| Authors: | Dr Cédric Reuter Dr Robert Opitz Dr Arne Soicke Stephan Dohmen Matthias Barone Slim Chiha Marco Tobias Klein Dr Jörg‐Martin Neudörfl Dr Ronald Kühne Prof?Dr Hans‐Günther Schmalz |
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| Affiliation: | 1. Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany);2. Leibniz‐Institut für Molekulare Pharmakologie (FMP), Campus Berlin‐Buch, Robert‐R?ssle‐Str. 10, 13125 Berlin (Germany) |
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| 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. |
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| Keywords: | amino acids conformation analysis helical structures protein– protein interactions peptidomimetics |
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