A diketopiperazine (DKP), also known as a ''dioxopiperazine'' or ''piperazinedione'', is a class of organic compounds related to

piperazine Piperazine () is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste. The piperazines are a broad ...

but containing two

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

linkages. DKP's are the smallest known class of cyclic peptide. Despite their name, they are not ketones, but amides. Three regioisomers are possible, differing in the locations of the

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

groups.

* One isomer is an

oxamide Oxamide is the organic compound with the formula . This white crystalline solid is soluble in ethanol, slightly soluble in water and insoluble in diethyl ether. Oxamide is the diamide derived from oxalic acid. Preparation Oxamide is produced f ...

obtained from

ethylenediamine Ethylenediamine (abbreviated as en when a ligand) is the organic compound with the formula C2H4(NH2)2. This colorless liquid with an ammonia-like odor is a basic amine. It is a widely used building block in chemical synthesis, with approximately ...

. * 2,5-Diketopiperazines are cyclodipeptides often obtainable via condensation of two α-

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

. * 2,6-Diketopiperazines may be viewed as cyclized

imide In organic chemistry, an imide is a functional group consisting of two acyl groups bound to nitrogen. The compounds are structurally related to acid anhydrides, although imides are more resistant to hydrolysis. In terms of commercial applications, ...

derivatives derived from iminodiacetic acids. Of these three isomeric diketopiperazines, the 2,5-derivatives have attracted the greatest interest. Due to their appearance in biologically active

natural products A natural product is a natural Chemical compound, compound or chemical substance, substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural product ...

, medicinal chemists have been inspired to use DKPs to circumvent the poor physical and metabolic properties of peptides in the course of

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...

Natural sources

DKPs are synthesized by a wide range of organisms, including bacteria, fungi, more complex marine microorganisms, and even mammals. However, 90% of

gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

synthesize these molecules, making them the target of most studies.

Biological activity

DKPs have been shown to inhibit the activities of bacteria, fungi, viruses, and potentially protozoa, as well as exhibit antitumor and antiprion properties. The molecule

glionitrin Glionitrin A is an antibiotic-anticancer compound made by microbes found in an abandoned mine. The total synthesis of (−)-glionitrin A was reported by Daniel Strand and co-workers in 2021. References {{organic-compound-stub Nitro compounds ...

, for instance, proved to be very effective against methicillin-resistant ''Staphylococcus aureus'' (MRSA), in addition to four different human cancer cell lines ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

''. As antivirals, however, DPKs appear to have a poor outlook when compared to those already on the market. Despite the great potential for diversity in this class of molecules, natural DPKs containing

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

are significantly overrepresented among those known to be biologically active. There also appears to be some bias with regards to stereochemistry, as DD-stereoisomers tend to display stronger antibiotic capabilities.

References

{{Reflist Functional groups