2,5-Diketopiperazine

General structure of diketopiperazines
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.[1] 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]

2,5-Diketopiperazines are commonly biosynthesized from amino acids by a variety of organisms, including mammals, and are considered to be secondary metabolites.[3] 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.[1]

The rings may also be prepared synthetically via a wide range of techniques.[1][3][4] The simplest of which is the formation of the dipeptide followed by dehydrative cyclisation, other methods include modified Ugi reactions.[5]

Applications

Several drugs have been commercialized containing the diketopiperazine backbone.[6]

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.[1][3] Both natural and synthetic 2,5-diketopiperazines exhibit a variety of biological activities including antitumor,[7] antiviral,[8] antifungal[9] and antibacterial[10] 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.[11]

References

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  1. 1 2 3 4 Borthwick, Alan D. (11 July 2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews 112 (7): 3641–3716. doi:10.1021/cr200398y. PMID 22575049.
  2. ↑ Corey, R. B. (1938). "Crystal Structure of Diketopiperazine". Journal of the American Chemical Society 60 (7): 1598–1604. doi:10.1021/ja01274a023.
  3. 1 2 3 Martins, M. B.; Carvalho, I. (2007). "Diketopiperazines: Biological Activity and Synthesis". Tetrahedron 63 (40): 9923–9932. doi:10.1016/j.tet.2007.04.105.
  4. ↑ Fischer, Peter M. (January 2003). "Diketopiperazines in peptide and combinatorial chemistry". Journal of Peptide Science 9 (1): 9–35. doi:10.1002/psc.446.
  5. ↑ Ugi, Ivar (27 January 1962). "The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions". Angewandte Chemie International Edition in English 1 (1): 8–21. doi:10.1002/anie.196200081.
  6. ↑ Jiang, C.-S.; Muller, W. E. G.; Schroder, H. C.; Guo, Y.-W., "Disulfide- and Multisulfide-Containing Metabolites from Marine Organisms", Chem. Rev. 2012, 112, 2179-2207. doi:10.1021/cr200173z
  7. ↑ Nicholson, B.; Lloyd, G. K.; Miller, B. R.; Palladino, M. A.; Kiso, Y.; Hayashi, Y.; Neuteboom, S. T. (2006). "NPI-2358 is a Tubulin-depolymerizing Agent: In-vitro Evidence for Activity as a Tumor Vascular-Disrupting Agent". Anti-Cancer Drugs 17 (1): 25–31. doi:10.1097/01.cad.0000182745.01612.8a. PMID 16317287.
  8. ↑ Sinha, S.; Srivastava, R.; de Clercq, E.; Singh, R. K. (2004). "Synthesis and Antiviral Properties of Arabino and Ribonucleosides of 1,3-Dideazaadenine, 4-Nitro-1,3-dideazapurine and Diketopiperazine". Nucleosides, Nucleotides and Nucleic Acids 23 (12): 1815–1824. doi:10.1081/NCN-200040614. PMID 15628741.
  9. ↑ Houston, D. R.; Synstad, B.; Eijsink, V. G.; Stark, M. J.; Eggleston, I. M.; van Aalten, D. M. (2004). "Structure-Based Exploration of Cyclic Dipeptide Chitinase Inhibitors". Journal of Medicinal Chemistry 47 (23): 5713–5720. doi:10.1021/jm049940a. PMID 15509170.
  10. ↑ Kwon, O. S.; Park, S. H.; Yun, B.-S.; Pyun, Y. R.; Kim, C.-J. (2000). "Cyclo(Dehydroala-L-Leu), an α-Glucosidase Inhibitor from Penicillium sp. F70614" (pdf). Journal of Antibiotics 53 (9): 954–958. doi:10.7164/antibiotics.53.954. PMID 11099229.
  11. ↑ Thomas Wirth "New Strategies to α-Alkylated α-Amino Acids" Angewandte Chemie International Edition in English 1997, Volume 36, Issue 3, pages 225–227. doi:10.1002/anie.199702251
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