Volume 21, Issue 23 p. 8464-8470
Full Paper

Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation

Dr. Cédric Reuter

Dr. Cédric Reuter

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Dr. Robert Opitz

Dr. Robert Opitz

Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)

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Dr. Arne Soicke

Dr. Arne Soicke

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Stephan Dohmen

Stephan Dohmen

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Matthias Barone

Matthias Barone

Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)

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Slim Chiha

Slim Chiha

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Marco Tobias Klein

Marco Tobias Klein

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Dr. Jörg-Martin Neudörfl

Dr. Jörg-Martin Neudörfl

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Dr. Ronald Kühne

Corresponding Author

Dr. Ronald Kühne

Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)

Ronald Kühne, Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)

Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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Prof. Dr. Hans-Günther Schmalz

Corresponding Author

Prof. Dr. Hans-Günther Schmalz

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

Ronald Kühne, Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)

Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)

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First published: 23 April 2015
Citations: 18

Graphical Abstract

ProMoting proline: The spiro-tricyclic scaffold ProM-2, which is designed to be a diproline analogue locked in a polyproline type II (PPII) conformation, can be synthesized from vinylproline building blocks. ProM-2 serves as a module for the development of small molecules that specifically interfere with PPII helix-mediated protein–protein interactions (see figure).

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.