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.

Diketopiperazines (DKP) are a class of cyclic organic compounds that result from peptide bonds between two amino acids to form a lactam. They are the smallest possible cyclic peptides.

A diketopiperazine was the first peptide to have its complete three-dimensional structure described, in work undertaken at Caltech by Robert Corey in the 1930s. Corey studied the cyclic anhydride of the dipeptide glycylglycine.^[1]

Diketopiperazines are commonly biosynthesized from amino acids by different organisms, including mammals, and are considered to be secondary metabolites.^[2] Some protease enzymes, such as dipeptidyl peptidases, cleave the terminal ends of proteins to generate dipeptides which naturally cyclize to form diketopiperazines.

Due to their rigid structure, chiral nature, and varied side chains, diketopiperazines are an attractive scaffold for drug design.^[2] Both natural and synthetic diketopiperazines have a wide variety of biological activities including antitumor,^[3] antiviral,^[4] antifungal^[5] and antibacterial^[6] activities.

References

1. ^ Corey, Robert B. (1938). "Crystal structure of diketopiperazine". Journal of the American Chemical Society 60 (7): 1598–1604. doi:10.1021/ja01274a023. 
2. ^ ^{a b} Maristela B. Martins and Ivone Carvalho (2007). "Diketopiperazines: biological activity and synthesis". Tetrahedron 63 (40): 9923–9932. doi:10.1016/j.tet.2007.04.105. 
3. ^ Nicholson, B.; Lloyd, GK; Miller, BR; Palladino, MA; Kiso, Y; Hayashi, Y; Neuteboom, ST (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. 
4. ^ Sinha, Sarika; Srivastava, Richa; De Clercq, Erik; Singh, Ramendra K. (2004). "Synthesis and Antiviral Properties of Arabino and Ribonucleosides of 1,3-Dideazaadenine, 4-Nitro-1,3-dideazaadenine and Diketopiperazine". Nucleosides, Nucleotides & Nucleic Acids 23 (12): 1815–1824. doi:10.1081/NCN-200040614. 
5. ^ Houston, Douglas R.; Synstad, Bjornar; Eijsink, Vincent G. H.; Stark, Michael J. R.; Eggleston, Ian M.; van Aalten, Daan M. F. (2004). "Structure-Based Exploration of Cyclic Dipeptide Chitinase Inhibitors". Journal of Medicinal Chemistry 47 (23): 5713–5720. doi:10.1021/jm049940a. PMID 15509170. 
6. ^ Kwon, Oh Sung; Park, Sang Ho; Yun, Bong-Sik; Pyun, Yu Ryang; Kim, Chang-Jin (2000). "Cyclo(dehydroala-L-Leu), an a-glucosidase inhibitor from Penicillium sp. F70614". Journal of Antibiotics 53 (9): 954–958. PMID 11099229.