Design and Synthesis of Building Blocks for PPII‐Helix Secondary‐Structure Mimetics: A Stereoselective Entry to 4‐Substituted 5‐Vinylprolines

Chiha, Slim; Soicke, Arne; Barone, M.; Müller, Mat­thias; Bruns, Judith; Opitz, Robert; Neudörfl, Jörg‐Martin; Kühne, Ronald; Schmalz, Hans‐Günther

doi:10.1002/ejoc.201701584

Cited by 10 publications

(18 citation statements)

References 49 publications

(21 reference statements)

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“…The compounds employed in this study were synthesized by modular assembly of the building blocks using established coupling protocols ( 40 ). The required ProM scaffolds ProM-1 ( 41 , 43 ), ProM-2 ( 45 ), ProM-9 ( 46 ), ProM-13 ( 46 ), ProM-15 ( 47 ), and ProM-17 ( 47 ) ( Fig. 1 B ) were synthesized as separately published.…”

Section: Resultsmentioning

confidence: 99%

“…For this reason the alkylated derivatives of ProM-1, i.e., ProM-9 and ProM-13 ( Fig. 1 B ), were synthesized ( 46 ) and used to prepare the desired inhibitors 6 and 7 ( Table 1 ). Affinity measurements then showed that both inhibitors outperformed 1 substantially and lowered the

to 380 nM ( 6 ) and 120 nM ( 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…In the course of our research into small molecules as potential inhibitors of protein–protein interactions ( 39 ) we recently in silico designed and stereo-selectively synthesized scaffolds, coined ProMs, which mimic pairs of prolines in PPII conformation ( 40 ). The modular combination of different ProMs thereby allowed us to generate nonpeptidic secondary-structure mimetics that fulfill the steric requirements of the addressed proline-rich motif-recognizing domain ( 41 – 47 ). For the EVH1 domain, our proof-of-concept study yielded a canonically binding, nontoxic, cell-membrane-permeable, 706-Da inhibitor 1 ( Fig.…”

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confidence: 99%

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Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells

Barone

Müller

Chiha

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein–protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor (Kd=120 nM,MW=734Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein–protein interaction involved in actin filament processing and cell migration.

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Section: Resultsmentioning

confidence: 99%

to 380 nM ( 6 ) and 120 nM ( 7 ).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells

Barone

Müller

Chiha

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…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.…”

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confidence: 99%

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

Dohmen

Reiher

Albat

et al. 2020

Chemistry A European J

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A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.

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“…In the original article, we inadvertently swapped structures 8 and 9 at the top of Table (on page 457). We apologize for this error.…”

Section: Diastereoselective Vinylation Of 5‐methoxy‐prolines Of Typementioning

confidence: 99%