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A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 4: Core Fragments with Two Halide Leaving Groups Featuring Side Chains of Proteinogenic Amino Acids

ABSTRACT: Abstract Teraryl‐based α‐helix mimetics have proven to be useful compounds for the inhibition of protein‐protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl‐based α‐helix mimetics using a benzene core unit featuring two halide leaving groups of differentiated reactivity in the Pd‐catalyzed cross‐coupling used for teraryl assembly. The use of para‐bromo iodoarene core fragments resolved the issue of hydrolysis during cross‐coupling that was observed when using triflate as a leaving group. We report a complete set of para‐bromoiodoarene core fragments decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr and Val). In order to be compatible with general cross‐coupling conditions, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks. A series of para‐bromoiodoarene compounds decorated with the side chains of all proteinogenic amino acids is reported. These fragments serve as building blocks for the modular assembly of teraryl‐based α‐helix mimetics via sequential Pd cross‐coupling. Compared to our established iodotriflate approach, the new building blocks showed higher stability and better reactivity under cross‐coupling conditions.

SUBMITTER: Trobe M

PROVIDER: S-EPMC9304293 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 3: Iodophenyltriflate Core Fragments Featuring Side Chains of Proteinogenic Amino Acids

Project description:Abstract Teraryl‐based α‐helix mimetics have proven to be useful compounds for the inhibition of protein‐protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl‐based α‐helix mimetics using a benzene core unit featuring two leaving groups of differentiated reactivity in the Pd‐catalyzed cross‐coupling used for teraryl assembly. In previous publications we have introduced the methodology of 4‐iodophenyltriflates decorated with the side chains of some of the proteinogenic amino acids. We herein report the core fragments corresponding to the previously missing amino acids Arg, Asn, Asp, Met, Trp and Tyr. Therefore, our set now encompasses all relevant amino acid analogues with the exception of His. In order to be compatible with the triflate moiety, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks. Additionally, cross‐coupling procedures for the assembly of teraryls were investigated. A series of iodophenyltriflate compounds decorated with the side chains of the proteinogenic amino acids Arg, Asn, Asp, Met, Trp and Tyr is reported. These fragments the set of building blocks for the modular assembly of teraryl‐based alpha‐helix mimetics through sequential Pd cross‐coupling.

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A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 5: A Complete Set of Pyridine Boronic Acid Pinacol Esters Featuring Side Chains of Proteinogenic Amino Acids.

Project description:Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics using pyridine containing boronic acid building blocks to increase the water solubility. Following our initial publication in which we have introduced the methodology in combination with sequential Pd-catalyzed cross-coupling for teraryl assembly, we can now report a complete set of pyridine based boronic acid building blocks decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr, Val) to complement the core fragment set. For a representative set of teraryls we have studied the influence of the pyridine rings on the solubility of the assembled oligoarenes.

| S-EPMC9304165 | biostudies-literature

Effects of side chains in helix nucleation differ from helix propagation.

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Anchor side chains of short peptide fragments trigger ligand-exchange of class II MHC molecules.

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Project description:?-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide ?-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.

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In vivo modulation of ubiquitin chains by N-methylated non-proteinogenic cyclic peptides.

Project description:Cancer and other disease states can change the landscape of proteins post-translationally tagged with ubiquitin (Ub) chains. Molecules capable of modulating Ub chains are potential therapeutic agents, but their discovery represents a significant challenge. Recently, it was shown that de novo cyclic peptides, selected from trillion-member random libraries, are capable of binding particular Ub chains. However, these peptides were overwhelmingly proteinogenic, so the prospect of in vivo activity was uncertain. Here, we report the discovery of small, non-proteinogenic cyclic peptides, rich in non-canonical features like N-methylation, which can tightly and specifically bind Lys48-linked Ub chains. These peptides engage three Lys48-linked Ub units simultaneously, block the action of deubiquitinases and the proteasome, induce apoptosis in vitro, and attenuate tumor growth in vivo. This highlights the potential of non-proteinogenic cyclic peptide screening to rapidly find in vivo-active leads, and the targeting of ubiquitin chains as a promising anti-cancer mechanism of action.

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Aromatic Foldamer Helices as ?-Helix Extended Surface Mimetics.

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Probing Protein Surfaces: QSAR Analysis with Helix Mimetics.

Project description:α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

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Modulation of p-cyanophenylalanine fluorescence by amino acid side chains and rational design of fluorescence probes of alpha-helix formation.

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