Diketopiperazine

A diketopiperazine (DKP), also known as a dioxopiperazine or piperazinedione, is a class of organic molecules in which the two nitrogen atoms of a piperazine 6-membered ring are part of amide linkages. There are three regioisomers possible, differing in the locations of the two carbonyl groups around the ring. While these isomers share a piperazine core, optimal strategies for their synthesis differ.[1] The 2,3-diketopiperazines may be viewed as oxamides obtained from ethylenediamine. 2,5-Diketopiperazines are cyclodipeptides often obtainable via condensation of two α-amino acids. 2,6-Diketopiperazines may be viewed as cyclized imide derivatives derived from iminodiacetic acids. Of these three isomeric diketopiperazines, the 2,5-derivatives have attracted the greatest interest.[2]

DKPs can be visualized as α-amino amides where the nitrogen atoms are constrained into a six membered ring:

The diketopiperazines:2,3-, 2,5, and 2,6-isomers.

As a result of the structural similarities of DKPs to peptides[3] and their appearance in biologically active natural products, medicinal chemists have been inspired to use DKPs to circumvent the poor physical and metabolic properties of peptides in the course of drug discovery.

References

  1. ↑ Dinsmore JC, Beshore DC. (2002). "Recent Advances in the Synthesis of Diketopiperazines". Tetrahedron. 58 (17): 3297–3312. doi:10.1016/S0040-4020(02)00239-9.
  2. ↑ Borthwick, A. D., "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products", Chem. Rev. 2012, volume 112, pp. 3641-3716. doi:10.1021/cr200398y
  3. ↑ Witiak DT, Wei Y. (1990). "Dioxopiperazines: chemistry and biology". Progress in Drug Research. 35: 249–363. ISBN 3-7643-2499-6. PMID 2290982.
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