The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

Abstract

SummaryAiming at restricting the conformational freedom of tryptophan-containing peptide ligands, we designed a THBC (tetrahydro-β-carboline)-DKP (diketopiperazine)-based peptidomimetic scaffold capable of arranging in an unusual α-turn conformation. The synthesis is based on a diastereoselective Pictet–Spengler condensation to give the THBC core, followed by an intramolecular lactamization to complete the tetracyclic THBC-DKP fused ring system. The presence of conformers bearing the intramolecular thirteen-membered hydrogen bond that characterizes the α-turn structure is confirmed by 1H NMR conformational studies. To the best of our knowledge, this scaffold represents one of the rare examples of a designed constrained α-turn mimic.

Oxa–diketopiperazines: Access and Conformational Analysis of Potential Turn Inducers

“…Since cyclic scaffolds such as proline analogues and diketopiperazine (DKP), are well known structures exhibiting turn inducer properties, we ambitioned that the 1,2,5‐Oxd skeleton could be defined as an alternative sources of turn inducer. Among the turns present in nature, the β‐turn is one of the major secondary structural element of proteins, playing an essential role in folding and in recognition .…”

Synthetic turn mimetics and hairpin nucleators: Quo Vadimus?

“…2h), 44 diketopiperazines 110 ( Fig. 2i), 45 hydroxyproline-derived diketopiperazine template, 46 tetrahydro-β-carboline-diketopiperazine-based peptidomimetic scaffold, 47 sugars (Fig. 2j), 48 and hydroxypyrrolizidinone, 49 to name a few.…”

The Role of N‐Methyl Squaramides in a Hydrogen‐Bonding Strategy to Fold Peptidomimetic Compounds

“…Alternatively, α‐turns are unusual secondary structures in proteins that enable 13‐membered hydrogen‐bonded rings to be stabilized by internal hydrogen bonds that correspond to tighter structures as β‐turns. Although they have a unique role in relevant bioactive peptides, there are just a few examples of synthetic modules mimicking α‐turns because of the difficulty of reproducing its features in synthetic modules . Therefore, access to modules that could mimic the formation of α‐ and β‐turns in bioactive peptidomimetic compounds is of significant interest.…”

“…Although they have au nique role in relevant bioactive peptides, there are just af ew examples of synthetic modules mimicking a-turns because of the difficultyo fr eproducingi ts features in synthetic modules. [15,16] Therefore, access to modules that could mimict he formation of a-a nd b-turns in bioactive peptidomimetic compounds is of significant interest. Many different scaffolds mimic b-turn fragments.…”