Diketopiperazine

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

A diketopiperazine (DKP), also known as a dioxopiperazine or piperazinedione, is a class of organic compounds related to piperazine but containing two amide linkages. DKP's are the smallest known class of cyclic peptide. [1] Despite their name, they are not ketones, but amides. Three regioisomers are possible, differing in the locations of the carbonyl groups.

Contents

Retosiban is a diketopiperazine being investigated as an oral drug. Retosiban structure.svg
Retosiban is a diketopiperazine being investigated as an oral drug.

Of these three isomeric diketopiperazines, the 2,5-derivatives have attracted the greatest interest. [3] [4] Due to 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.

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 synthesize these molecules, making them the target of most studies. [1]

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, for instance, proved to be very effective against methicillin-resistant Staphylococcus aureus (MRSA), in addition to four different human cancer cell lines in vitro . As antivirals, however, DPKs appear to have a poor outlook when compared to those already on the market. [1]

Despite the great potential for diversity in this class of molecules, natural DPKs containing proline 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. [1]

Related Research Articles

Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; the terms are equivalent in the literature. Larger structures such as nucleic acids and proteins, and many polysaccharides are not small molecules, although their constituent monomers are often considered small molecules. Small molecules may be used as research tools to probe biological function as well as leads in the development of new therapeutic agents. Some can inhibit a specific function of a protein or disrupt protein–protein interactions.

<span class="mw-page-title-main">Drug discovery</span> Process by which new candidate medications are discovered

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.

<span class="mw-page-title-main">Drug design</span> Inventive process of finding new medications based on the knowledge of a biological target

Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.

<span class="mw-page-title-main">Dipeptide</span> Shortest peptide molecule, containing two amino acids joined by a single peptide bond

A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologically important, and some are both physiologically and commercially significant. A well known dipeptide is aspartame, an artificial sweetener.

Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynthesis, and application of polyketides has evolved. It is a large and diverse group of secondary metabolites caused by its complex biosynthesis which resembles that of fatty acid synthesis. Because of this diversity, polyketides can have various medicinal, agricultural, and industrial applications. Many polyketides are medicinal or exhibit acute toxicity. Biotechnology has enabled discovery of more naturally-occurring polyketides and evolution of new polyketides with novel or improved bioactivity.

<span class="mw-page-title-main">Natural product</span> Chemical compound or substance produced by a living organism, found in nature

A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients.

Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. In contrast to biochemistry, which involves the study of the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology deals with chemistry applied to biology.

Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid that is soluble in water. Also known as 1,3-diazanaphthalene, quinazoline received its name from being an aza derivative of quinoline. Though the parent quinazoline molecule is rarely mentioned by itself in technical literature, substituted derivatives have been synthesized for medicinal purposes such as antimalarial and anticancer agents. Quinazoline is a planar molecule. It is isomeric with the other diazanaphthalenes of the benzodiazine subgroup: cinnoline, quinoxaline, and phthalazine. Over 200 biologically active quinazoline and quinoline alkaloids are identified.

<span class="mw-page-title-main">Enzyme inhibitor</span> Molecule that binds to an enzyme and decreases its activity

An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a specific chemical reaction by binding the substrate to its active site, a specialized area on the enzyme that accelerates the most difficult step of the reaction.

<span class="mw-page-title-main">Cyclic peptide</span>

Cyclic peptides are polypeptide chains which contain a circular sequence of bonds. This can be through a connection between the amino and carboxyl ends of the peptide, for example in cyclosporin; a connection between the amino end and a side chain, for example in bacitracin; the carboxyl end and a side chain, for example in colistin; or two side chains or more complicated arrangements, for example in amanitin. Many cyclic peptides have been discovered in nature and many others have been synthesized in the laboratory. Their length ranges from just two amino acid residues to hundreds. In nature they are frequently antimicrobial or toxic; in medicine they have various applications, for example as antibiotics and immunosuppressive agents. Thin-Layer Chromatography (TLC) is a convenient method to detect cyclic peptides in crude extract from bio-mass.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

<span class="mw-page-title-main">Epelsiban</span> Chemical compound

Epelsiban is an orally bioavailable drug which acts as a selective and potent oxytocin receptor antagonist. It was initially developed by GlaxoSmithKline (GSK) for the treatment of premature ejaculation in men and then as an agent to enhance embryo or blastocyst implantation in women undergoing embryo or blastocyst transfer associated with in vitro fertilization (IVF)., and was also investigated for use in the treatment of adenomyosis.

<span class="mw-page-title-main">Retosiban</span> Chemical compound

Retosiban also known as GSK-221,149-A is an oral drug which acts as an oxytocin receptor antagonist. It is being developed by GlaxoSmithKline for the treatment of preterm labour. Retosiban has high affinity for the oxytocin receptor and has greater than 1400-fold selectivity over the related vasopressin receptors

2,5-Diketopiperazine is an organic compound with the formula (NHCH2C(O))2. The compound features a six-membered ring containing two amide groups at opposite positions in the ring. It was first compound containing a peptide bond to be characterized by X-ray crystallography in 1938. It is the parent of a large class of 2,5-Diketopiperazines (2,5-DKPs) with the formula (NHCH2(R)C(O))2 (R = H, CH3, etc.). They are ubiquitous peptide in nature. They are often found in fermentation broths and yeast cultures as well as embedded in larger more complex architectures in a variety of natural products as well as several drugs. In addition, they are often produced as degradation products of polypeptides, especially in processed foods and beverages. They have also been identified in the contents of comets.

<span class="mw-page-title-main">Stephacidin</span>

Stephacidin A and B are antitumor alkaloids isolated from the fungus Aspergillus ochraceus that belong to a class of naturally occurring 2,5-diketopiperazines. This unusual family of fungal metabolites are complex bridged 2,5-diketopiperazine alkaloids that possess a unique bicyclo[2.2.2]diazaoctane core ring system and are constituted mainly from tryptophan, proline, and substituted proline derivatives where the olefinic unit of the isoprene moiety has been formally oxidatively cyclized across the α-carbon atoms of a 2,5-diketopiperazine ring. The molecular architecture of stephacidin B, formally a dimer of avrainvillamide, reveals a complex dimeric prenylated N-hydroxyindole alkaloid that contains 15 rings and 9 stereogenic centers and is one of the most complex indole alkaloids isolated from fungi. Stephacidin B rapidly converts into the electrophilic monomer avrainvillamide in cell culture, and there is evidence that the monomer avrainvillamide interacts with intracellular thiol-containing proteins, most likely by covalent modification.

<span class="mw-page-title-main">Bottromycin</span> Chemical compound

Bottromycin is a macrocyclic peptide with antibiotic activity. It was first discovered in 1957 as a natural product isolated from Streptomyces bottropensis. It has been shown to inhibit methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) among other Gram-positive bacteria and mycoplasma. Bottromycin is structurally distinct from both vancomycin, a glycopeptide antibiotic, and methicillin, a beta-lactam antibiotic.

Medicinal fungi are fungi that contain metabolites or can be induced to produce metabolites through biotechnology to develop prescription drugs. Compounds successfully developed into drugs or under research include antibiotics, anti-cancer drugs, cholesterol and ergosterol synthesis inhibitors, psychotropic drugs, immunosuppressants and fungicides.

<span class="mw-page-title-main">Brevianamide F</span> Chemical compound

Brevianamide F , also known as cyclo-(L-Trp-L-Pro), belongs to a class of naturally occurring 2,5-diketopiperazines. It is the simplest member and the biosynthetic precursor of a large family of biologically active prenylated tryptophan-proline 2,5-diketopiperazines that are produced by the fungi A. fumigatus and Aspergillus sp. It has been isolated from the bacterium Streptomyces sp. strain TN58 and shown to possess activity against the Gram-positive bacteria S. aureus and Micrococcus luteus. It has also been isolated from Bacillus cereus associated with the entomopathogenic nematode Rhabditis (Oscheius) sp. and shown to have antifungal activity against T. rubrum, C. neoformans, and C. albicans, better than amphotericin B. Although the proline 2,5-diketopiperazines are the most abundant and structurally diverse 2,5-diketopiperazines found in food, cyclo(L-Trp-L-Pro) has only been found as a minor 2,5-diketopiperazine (8.2 ppm) in autolyzed yeast extract. Initially, cyclo(L-Trp-L-Pro) and its DL, LD, and DD isomers showed potential for use in the treatment of cardiovascular dysfunction, but they were later shown to be hepatotoxic.

<span class="mw-page-title-main">Bicyclomycin</span> Antibiotic

Bicyclomycin (Bicozamycin) is a broad spectrum antibiotic active against Gram-negative bacteria and the Gram-positive bacterium, Micrococcus luteus that was isolated from Streptomyces sapporonesis and Streptomyces aizumenses in 1972. It belongs to a class of naturally occurring 2,5-diketopiperazines, that are among the most numerous of all the naturally occurring peptide antibiotics. This clinically useful antibiotic is rapidly absorbed in humans when given intramuscularly, has low toxicity and has been used to treat diarrhea in humans and bacterial diarrhea in calves and pigs.

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They are proteins covalenently bound to fatty acid chains, often granting them an interface for interacting with biological membranes. They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

References

  1. 1 2 3 4 Carvalho, M. P. de; Abraham, W.-R. (2012). "Antimicrobial and Biofilm Inhibiting Diketopiperazines". Current Medicinal Chemistry. 19 (21): 3564–3577. doi:10.2174/092986712801323243. PMID   22709011.
  2. Borthwick AD, Liddle J (January 2013). "Retosiban and Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". In Domling A (ed.). Methods and Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery. Weinheim: Wiley-VCH. pp. 225–256. ISBN   978-3-527-33107-9.
  3. Borthwick, A. D. (2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chem. Rev. 112 (7): 3641–716. doi:10.1021/cr200398y. PMID   22575049.
  4. Witiak DT, Wei Y. (1990). "Dioxopiperazines: chemistry and biology". Progress in Drug Research. 35: 249–363. doi:10.1007/978-3-0348-7133-4_7. ISBN   3-7643-2499-6. PMID   2290982.