Bifunctional 2,5‐Diketopiperazines as Rigid Three‐Dimensional Scaffolds in Receptors and Peptidomimetics

Abstract

2,5‐Diketopiperazines (DKPs) are heterocyclic scaffolds easily accessible from α‐amino acids and characterized by rather flat six‐membered‐ring cores that can be functionalized at four positions (N1, N4, C3, C6), two of which are stereogenic centers (C3, C6). In this microreview, the syntheses and the solution conformations of several DKP scaffolds are discussed with regard to their application as two‐armed receptors for the selective recognition of small peptides and anions and as peptidomimetics mimicking topologically relevant elements of protein secondary structure (e.g., β‐turns, β‐hairpins, and α‐helices). In many cases the properties of these compounds can be interpreted in terms of their conformationally defined three‐dimensional structures, which can be assessed by spectroscopic and computational methods.

New Chlorinated 2,5-Diketopiperazines from Marine-Derived Bacteria Isolated from Sediments of the Eastern Mediterranean Sea

“…The DKP chiral scaffold is attractive for drug design due to its simplicity, high stability (resistance to proteolysis), conformational rigidity, and remarkable structural diversity [18]. DKPs are readily accessible by chemical synthesis, constituting an excellent model for theoretical studies and an are readily accessible by chemical synthesis, constituting an excellent model for theoretical studies and an important pharmacophore in medicinal chemistry [4,13,19]. Moreover, they are employed as starting materials for the synthesis of many natural products, such as alkaloids [18].…”

Synthesis and Biological Evaluation of Epidithio-, Epitetrathio-, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-epi-ent-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

“…1 Numerous have been discovered from natural sources while many more have been synthesized in the laboratory for biological investigations and drug discovery purposes. 1 The 2,5-diketopiperazine structural motif constitutes a unique scaffold upon which three dimensional molecules, including chiral ones, may be constructed, 1,2 thereby providing a useful alternative to the planar structural motifs commonly found in drugs and drug candidates, the latter being often far from ideal in terms of pharmacological properties. 3 …”

Designing Peptidomimetics

“…It can be thought also in using a tricycle scaffold by closing a ring structure between two consecutive prolines. In this direction, the derived diketopiperazine template has successfully been used to design molecules that works as model receptors of tripeptides and that could be used pharmacologically as a non-competitive antagonist [180].…”