2,5-Diketopiperazine

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General structure of diketopiperazines

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Cyclic dipeptide (2,5-diketopiperazine ) from glycine and L-alanine (left). Cyclodi-L-prolyl (right) formed from two L-proline molecules. The cis-peptide bonds are drawn blue.

A 2,5-diketopiperazine (2,5-DKP) is a type of cyclic organic compound that results from peptide bonds between two amino acids to form a double lactam. They are the smallest cyclic peptides. In keeping with standard IUPAC organic nomenclature, the "2,5-" designates the atoms on the diketopiperazine ring that are the carbonyls.

Production

2,5-Diketopiperazine was the first peptide to have its complete three-dimensional structure described, in work undertaken Robert Corey in the 1930s.

2,5-Diketopiperazines are commonly biosynthesized from amino acids by a variety of organisms, including mammals, and are considered to be secondary metabolites. Some proteases, such as dipeptidyl peptidases, cleave the terminal ends of proteins to generate dipeptides, which naturally cyclize to form 2,5-diketopiperazines. They are also often produced as degradation products of polypeptides, especially in processed food and beverages.

The rings may also be prepared synthetically via a wide range of techniques. The simplest of which is the formation of the dipeptide followed by dehydrative cyclisation, other methods include modified Ugi reactions.

Applications

Several drugs have been commercialized containing the diketopiperazine backbone.

• Commercialized 2,5-Diketopiperazine-based drugs
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  Tadalafil

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  Gliotoxin

• Retosiban structure.svg

  Retosiban

• Epelsiban.svg

  Epelsiban

• Aplaviroc.svg

  Aplaviroc

Drug design scaffold

Due to their rigidity, chirality (except for the glycylglycine derivative), and varied side chains, 2,5-diketopiperazines are an attractive scaffolds for drug design. Both natural and synthetic 2,5-diketopiperazines exhibit a variety of biological activities including antitumor, antiviral, antifungal and antibacterial activities.

Reagents

The diketopiperazine obtains from glycylserine is a reagent for the preparation of C-alkylated derivatives of glycine. This approach is useful for the production of unnatural amino acids with stereochemical control. The diketopiperazine skeleton protects both the N and O termini of the glycine. For this application, the diketopiperazine is O-alkylated with concomitant N-deprotonation to give what is called the Schöllkopf reagent.