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.

Pd‐Catalyzed Asymmetric N‐Allylation of Amino Acid Esters with Exceptional Levels of Catalyst Control: Stereo‐Divergent Synthesis of ProM‐15 and Related Bicyclic Dipeptide Mimetics

“…In the course of our research into the inhibition of PPII helix‐mediated protein–protein interactions, we had designed and synthesized proline‐derived modules, such as ProM‐1 and ProM‐2 . This enabled us to develop a powerful inhibitor of the ena/VASP EVH1 domains involved in cell migration and chemotaxis (Figure )…”

“…Current investigations in our laboratory are focused on the further exploration of the developed N‐allylation protocol with respect to mechanistic aspects, the evaluation of the substrate scope and applications in natural‐product synthesis. Moreover, we are currently expanding our ProM toolbox with further ProM‐15 ‐related compounds, which are then incorporated as modules into PPII‐helix secondary structure mimetics acting as inhibitors of disease‐relevant protein–interactions.…”

“…In the course of our research into the inhibitiono fP PII helixmediated protein-protein interactions, we had designed and synthesized proline-derivedm odules, such as ProM-1 [1] and ProM-2. [2] This enabled us to develop ap owerful inhibitor of the ena/VASP EVH1 domains involvedi nc ell migrationa nd chemotaxis ( Figure 1). [3] More recently,m odeling studies suggested that compounds of type 1 (including ProM-15,f ormally derivedf rom ProM-1 by openingt he eastern proliner ing) would represent promising buildingb locks for an ew generation of EVH1 inhibitors, due to an enhanced flexibility of the C-terminus in combination with the option to address additional lipophilic or polar interactions ites at the protein surface by meanso ft he substituent R' (Scheme 1).…”

“…The value of the method was demonstrated in the stereo-divergents ynthesis of ProM-15 and related cyclic, proline-derived dipeptide mimetics, which represent attractive building blocks for the development of modularp eptide-inspired bioactive molecules with ad efined three-dimensional structure.C urrent investigationsi no ur laboratory are focused on the further exploration of the developed N-allylation protocol with respect to mechanistic aspects, the evaluation of the substrates cope and applications in natural-product synthesis. Moreover, we are currently expanding our ProMt oolbox [1][2][3]19] with further ProM-15-related compounds, which are then incorporated as modulesi nto PPII-helix secondary structure mimetics acting as inhibitors of disease-relevant protein-interactions.…”

Triple‐Helix‐Stabilizing Effects in Collagen Model Peptides Containing PPII‐Helix‐Preorganized Diproline Modules

“…[2] In the course of our previous studies aiming at the development of small-molecule inhibitors of the PPII helix recognizing Ena/VASP homology 1( EVH1) domain, we developed proline-derived modules (ProMs) ProM1 and ProM2 ( Figure 2). [27][28][29][30] Thed esign is based on the stereodefined covalent connection of two adjacent proline rings by aC 2 bridge to freeze the system in aP PII-helix-type conformation.…”