2,5-Diketopiperazine

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2,5-Diketopiperazine
2,5-Diketopiperazine num.svg
Names
IUPAC name
2,5-Piperazinedione
Preferred IUPAC name
Piperazine-2,5-dione
Other names
Cyclic dipeptides, cyclo-dipeptides, DKPs, CDPs 2,5 dioxopiperazines (DOPs), dipeptide anhydrides
Identifiers
3D model (JSmol)
3DMet
112112
ChEBI
ChEMBL
ChemSpider
EC Number
  • 203-411-5
217756
KEGG
PubChem CID
UNII
  • InChI=1S/C4H6N2O2/c7-3-1-5-4(8)2-6-3/h1-2H2,(H,5,8)(H,6,7)
    Key: BXRNXXXXHLBUKK-UHFFFAOYSA-N
  • C1C(=NCC(=N1)O)O
Properties
C4H6N2O2
Molar mass 114.104 g·mol−1
Melting point 311–312 °C (592–594 °F; 584–585 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. [1] 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. [2] In addition, they are often produced as degradation products of polypeptides, especially in processed foods and beverages. [3] They have also been identified in the contents of comets. [4]

Contents

Occurrence as natural products

There is a widespread occurrence of the 2,5-diketopiperazine core in biologically active natural products. The most structurally diverse 2,5-diketopiperazine natural products are based on tryptophan and proline modified by heterocyclisation and isoprenyl addition. These range from the hepatoxic brevianamide F (cyclo(L-Trp-L-Pro)) to the annulated tremorogenic verruculogen and the spiro-annulated spirotryprostatin B which represent a promising class of antimitotic arrest agents, to the structurally complex (+)-stephacidin A, a bridged 2,5-diketopiperazine that possess a unique bicyclo[2.2.2]diazaoctane core ring system and is active against the human colon HCT-116 cell line. [2]

Other bridged 2,5-diketopiperazines include bicyclomycin, an antibacterial agent used as food additives to prevent diarrhea in animals while the thio derivatives such as the cytotoxic bridged epipolythiodioxopiperazine are represented by gliotoxin. The unsaturated derivatives are illustrated by phenylahistin the anti-cancer microtubule binding agent, and the mycotoxin roquefortine C found in blue cheeses. [2]

Occurrence in foods and beverages

2,5-Diketopiperazines are often formed during chemical and thermal processing of food and beverages as the degradation products of polypeptides. They have been detected in stewed beef, beer, bread, Awamori spirits, cocoa, chicken essence, roasted coffee, Comte cheese, dried squid, aged saki and yeast extract. In food systems, 2,5-diketopiperazines have been shown to be important sensory compounds contributing to the taste of the final products and being perceived as astringent, salty, grainy, metallic or bitter. Although these range from proline, aromatic, aliphatic to polar 2,5-diketopiperazines, the proline 2,5-diketopiperazines are the most abundant and structurally diverse 2,5-diketopiperazines found in food. The valine derivative cyclo(L-Val-L-Pro) at a concentration of 1742 ppm, was identified as the most important bitter 2,5-diketopiperazine contributing to the bitter taste of roasted cocoa. It has also been found as one of the major 2,5-diketopiperazines in autolyzed yeast extract and stewed beef and is also present in chicken essence and coffee. [3] It has also been isolated from a variety of marine microorganisms and has been identified as an active LasI quorum-sensing signal molecule important for the plant growth promotion by Pseudomonas aeruginosa . [2] The most studied of all the simple 2,5-diketopiperazines is the histidyl-proline 2,5-diketopiperazine cyclo(L-His-L-Pro) [5] which is found in a variety of foods, with particularly high concentrations in fish and fish products. It is well absorbed orally, and crosses the blood–brain barrier via a non-saturable mechanism. It also occurs in humans [6] as a metabolite from the thyrotropin-releasing hormone (TRH) and exhibits a wide variety of central nervous system, endocrine, electrophysiological, and cardiovascular effects. [5] Derivatives of cyclo(L-His-L-Pro) have been studied extensively to develop therapeutic agents for neurodegeneration. [7] [2]

Structure and conformation

These cyclic dipeptides incorporate both donor and acceptor groups for hydrogen bonding. They are conformationally constrained nearly planar scaffolds. Diversity can be introduced at up to six positions and stereochemistry controlled at up to four positions. They are stable to proteolysis. These characteristics underpin theis biologically activity and utility in medicinal chemistry. As a consequence of their predominant biosynthetic origin from L-α-amino acids most naturally occurring 2,5-DKPs are cis configured as the cyclo(L-Xaa-L-Yaa) isomers. 2,5-DKPs epimerize under basic, acidic and thermal conditions. The composition of the cis and trans isomers in the equilibrium state varies widely depending on the bulk of the side chains, if a ring (e.g. proline) is present, or if the nitrogen atoms are alkylated . Although epimerization was historically an issue in the synthesis of 2,5-DKPs, several mild methods have been developed recently that avoid epimerization. [2]

Biosynthesis

2,5-DKPs are synthesized by a variety of organisms including humans. In general, they arise by the action of a tRNA-dependent cyclodipeptide synthases, a type of enzyme responsible for creating a cyclic amide linkage between two peptides. [8] The enzymes cyclodipeptide oxidase and S-adenosyl-methionine-dependent O/N methyltransferases act in tandem to chemically modify cyclic dipeptides. [8]

Synthesis

2,5-Diketopiperazines are typically prepared by one of three methods: amide bond formation, N-alkylation and C-acylation.

Methods of bond formation in ring closure synthesis of 2,5-DKPs Methods of ring closure in synthesis of 2,5-DKPs.svg
Methods of bond formation in ring closure synthesis of 2,5-DKPs

Amide bond formation

Most commonly 2,5-diketopiperazines are generated by cyclisation of dipeptides. In addition to the many methods of peptide synthesis, the Ugi reaction can be applied. Dipeptides with an ester terminus spontaneously cyclize often. Racemization can be problematic. [9] The Ugi reaction using an isonitrile, amino acid, aldehyde and amine, can produce a dipeptide in equally high yield and optical purity, to that formed by standard peptide couplings. [10] Commonly, an isonitrile is chosen to give a labile terminal amide to enable cyclization. For example, the direct 2,5-DKP ring formation via such an activated leaving group using the stable, easily accessible and versatile convertible isonitrile 1-isocyano-2-(2,2-dimethoxyethyl)-benzene 4 gave a one-pot synthesis of N-substituted 2,5-diketopiperazine's 7. [11]

One-pot synthesis of N-substituted 2,5-DKPs via indolamide One-pot synthesis of N-substituted 2,5-DKPs via indolamide.svg
One-pot synthesis of N-substituted 2,5-DKPs via indolamide

The mild acidic and chemoselective post Ugi activation of 5 involving simultaneous indolamide formation and tert-butoxycarbonyl (Boc) removal gives the active amide 6 which allows cyclization to 7 without affecting other peptidic or even ester moieties and with stereochemical retention of the chiral centers.

N-Alkylation

Intramolecular amide N-alkylation of alpha-haloacetamide amides 8 with ethanolic potassium hydroxide using ultrasonication gave the 2,5-diketopiperazines 9, where 8 was obtained by an Ugi reaction [12] between amines, aldehydes, isocyanides, and chloroacetic acid. However this route is limited by epimerization at the stereogenic centre and failure to obtain the 2,5-diketopiperazine ring if R1 = Alkyl.

Synthesis of 2,5-DKPs via N-Alkylation. Syn of 2,5-DKPs via Ugi-4CR N-Alkylation.svg
Synthesis of 2,5-DKPs via N-Alkylation.

C-Acylation

Formation of the 2,5-diketopiperazine ring by enolate acylation [13] was used in the construction of the 2,5-diketopiperazine ring in 11 by intramolecular cyclization of the enolate of 10 onto the carbonyl of the phenyl carbamate to give 11 in 90% yield.

Synthesis of 2,5-DKPs via intramolecular enolate acylation Synthesis of 2,5-DKPs via Enolate Acylation.svg
Synthesis of 2,5-DKPs via intramolecular enolate acylation

Reactions

Reactivity at carbon (C-3 and C-6)

Regio- and stereocontrolled C-functionalization of 2,5-diketopiperazines at C-3 and C-6 involve enolate, radical and cationic precursors (and N-acyliminium ion) and are sensitive to polar and steric effects.

Alkylation of enolates

Alkylation of the bis-paramethoxybenzyl (pMB) protected 2,5-DKP 1 using the base LHMDS and an alkyl bromide R1Br, gave the mono-alkylated derivative 2, which on further alkylation gave the symmetrical trans-disubstituted derivative 3

Enolate akylation at C-3 and C-6 Mono-and di-Alkylation of 2,5-Diketopiperazines.svg
Enolate akylation at C-3 and C-6

Halogenation and displacement

The 3-monobromides 6 and the 3,6-dibromides 5 are prepared from the benzyl protected 2,5-DKP 4 by radical halogenation with N-bromosuccinimide in carbon tetrachloride. Displacement of these labile bromides readily occurs with a range of nucleophiles SR, OR, NR2, alkyl and aryl to give 7 . [2]

Bromination of 2,5-Diketopiperazines followed by Nucleophilic displacement Bromination of 2,5-Diketopiperazines and Nucleophilic displacement.svg
Bromination of 2,5-Diketopiperazines followed by Nucleophilic displacement

Aldol addition

A one- or two-fold aldol condensation of N-acetylated 2,5-DKP 8 gives access to 3-dehydro-2,5-diketopiperazines 9 and 3,6-didehydro-2,5-diketopiperazines 10 and the condensation of 8 can controlled in a stepwise fashion using triethylamine in dimethylformamide to give the unsymmetrical 3,6-didehydro-2,5-diketopiperazines 10 (R1 = Ar1, R2 = Ar2). [2]

Aldol condensation with 2,5-Diketopiperazines Aldol reaction with 2,5-Diketopiperazines.svg
Aldol condensation with 2,5-Diketopiperazines

Reactivity at nitrogen

Alkylation

The most common method for alkylation of the lactam nitrogen of 2,5-diketopiperazines is based on the use of sodium hydride as base. However epimerisation can occur especially with proline-fused 2,5-diketopiperazines, even with milder methods such as under phase-transfer catalyst conditions for example 1 to 2. [2]

N-Alkylation of 2,5-Diketopiperazines and epimerisation N-Alkylation of 2,5-Diketopiperazines.svg
N-Alkylation of 2,5-Diketopiperazines and epimerisation

Reactivity at carbonyl carbons (C-2 and C-5)

Reduction

Reduction of the carbonyl groups of chiral 2,5-diketopiperazine with lithium aluminium hydride (LiAlH4) cleanly gives the corresponding chiral piperazines. For example, cyclo(L-Phe-L-Phe) 1 gives the chiral piperazine (2S,5S)-dibenzylpiperazine 2. [14]

Reduction of the carbonyl groups of 2,5-DKPs Reduction of 2,5-diketopiperazines to piperazines.svg
Reduction of the carbonyl groups of 2,5-DKPs

Dihydropyrazine and pyrazine synthesis

Reaction of the lactam-derived enol phosphates 4 of 2,5-diketopiperazines with palladium catalyzed reactions (reduction, Suzuki and Stille cross-coupling reactions) enables the synthesis of a range of functionalised 1,4-dihydropyrazines 5 which can be aromatized to 1,4-pyrazines 6 in the presence of acid. [15]

Synthesis of dihydropyrazines and pyrazines from 2,5-diketopiperazines via enol phosphates Synthesis of dihydropyrazines and pyrazines from 2,5-diketopiperazines.svg
Synthesis of dihydropyrazines and pyrazines from 2,5-diketopiperazines via enol phosphates

Biological Functions

2,5-DKPs have been shown to play a role in interspecies bacterial quorum sensing. For example, the 2,5-DKP cyclo(Phe-Pro) has been shown to play a role in the regulation of gene expression in multiple different species of bacteria including V. fishceri,V. cholera, Lactobacillus reuteri, Staphylococcus aureus, among others. [8]

Applications

Therapeutics

Numerous natural and synthetic 2,5-DKPs are bioactive. These small, conformationally rigid, chiral templates have multiple H-bond acceptor and donor functionality and have multiple sites for structural elaboration of diverse functional groups with defined stereochemistry. These characteristics not only enable them to bind with high affinity to a large variety of receptors, showing a broad range of biological activities, but also allow the development of the drug-like physicochemical properties required for the multiobjective optimization process of transforming a lead to a drug product. The structure–activity relationship (SAR) has been explored for many of these 2,5-DKP templates, and several have been developed into clinical drugs. These include tadalafil (a PDE5 inhibitor for erectile dysfunction), retosiban (an oxytocin antagonist for preterm labor), aplaviroc (a CCR5 antagonists for HIV), epelsiban (an oxytocin antagonist for premature ejaculation) and the experimental cancer drug plinabulin (NPI-2358/KPU-2) that is active in multidrug-resistant (MDR) tumor cell lines. [2]

Due to their role in bacterial communication, 2,5-DKPs have a potential to be used as a medicine to treat bacterial diseases. For example, the 2,5-DKP cis-cyclo(Leu-Tyr) has been shown to inhibit bacterial biofilm formation; this property can be utilized to treat infections caused by the bacterial biofilm formation. These chemicals can be used to imitate quorum sensing signals to regulate gene expression of pathogenic bacteria and help fight against bacterial infection. [8]

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. [16]

Related Research Articles

Pyrrole is a heterocyclic, aromatic, organic compound, a five-membered ring with the formula C4H4NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3. Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as heme.

The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877 to attach substituents to an aromatic ring. Friedel–Crafts reactions are of two main types: alkylation reactions and acylation reactions. Both proceed by electrophilic aromatic substitution.

<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.

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

<span class="mw-page-title-main">Robinson–Gabriel synthesis</span> Organic reaction

The Robinson–Gabriel synthesis is an organic reaction in which a 2-acylamino-ketone reacts intramolecularly followed by a dehydration to give an oxazole. A cyclodehydrating agent is needed to catalyze the reaction It is named after Sir Robert Robinson and Siegmund Gabriel who described the reaction in 1909 and 1910, respectively.

<span class="mw-page-title-main">Cyclic peptide</span> Peptide chains which contain a circular sequence of bonds

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 alpha-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.

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

Pseudoproline derivatives are artificially created dipeptides to minimize aggregation during Fmoc solid-phase synthesis of peptides.

<span class="mw-page-title-main">Erlenmeyer–Plöchl azlactone and amino-acid synthesis</span>

The Erlenmeyer–Plöchl azlactone and amino acid synthesis, named after Friedrich Gustav Carl Emil Erlenmeyer who partly discovered the reaction, is a series of chemical reactions which transform an N-acyl glycine to various other amino acids via an oxazolone.

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

Spirotryprostatin B is an indolic alkaloid found in the Aspergillus fumigatus fungus that belongs to a class of naturally occurring 2,5-diketopiperazines. Spirotryprostatin B and several other indolic alkaloids have been found to have anti-mitotic properties, and as such they have become of great interest as anti-cancer drugs. Because of this, the total syntheses of these compounds is a major pursuit of organic chemists, and a number of different syntheses have been published in the chemical literature.

The Schöllkopf method or Schöllkopf Bis-Lactim Amino Acid Synthesis is a method in organic chemistry for the asymmetric synthesis of chiral amino acids. The method was established in 1981 by Ulrich Schöllkopf. In it glycine is a substrate, valine a chiral auxiliary and the reaction taking place an alkylation.

<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">Enders SAMP/RAMP hydrazone-alkylation reaction</span>

The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric carbon-carbon bond formation reaction facilitated by pyrrolidine chiral auxiliaries. It was pioneered by E. J. Corey and D. Enders in 1976, and was further developed by D. Enders and his group. This method is usually a three-step sequence. The first step is to form the hydrazone between (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) and a ketone or aldehyde. Afterwards, the hydrazone is deprotonated by lithium diisopropylamide (LDA) to form an azaenolate, which reacts with alkyl halides or other suitable electrophiles to give alkylated hydrazone species with the simultaneous generation of a new chiral center. Finally, the alkylated ketone or aldehyde can be regenerated by ozonolysis or hydrolysis.

<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

In organic chemistry, the Fráter–Seebach alkylation is a diastereoselective alkylation of chiral beta-hydroxy esters using strong bases. The reaction was first published by Georg Fráter in 1979; in 1980, Dieter Seebach reported about a similar reaction with malic acid ester.

<span class="mw-page-title-main">Diketopiperazine</span> Class of chemical compounds

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. Despite their name, they are not ketones, but amides. Three regioisomers are possible, differing in the locations of the carbonyl groups.

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

Fumitremorgins are tremorogenic metabolites of Aspergillus and Penicillium, that belong to a class of naturally occurring 2,5-diketopiperazines.

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

Verruculogen is a mycotoxin produced by certain strains of aspergillus that belongs to a class of naturally occurring 2,5-diketopiperazines. It is an annulated analogue of cyclo(L-Trp-L-Pro) which belongs to the most abundant and structurally diverse class of tryptophan-proline 2,5-diketopiperazine natural products. It produces tremors in mice due to its neurotoxic properties. It also tested positive in a Salmonella/mammalian microsome assay and was shown to be genotoxic. It is a potent blocker of calcium-activated potassium channels.

<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.

<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">Ethyl cyanohydroxyiminoacetate</span> Chemical compound

Ethyl cyanohydroxyiminoacetate (oxyma) is the oxime of ethyl cyanoacetate and finds use as an additive for carbodiimides, such as dicyclohexylcarbodiimide (DCC) in peptide synthesis. It acts as a neutralizing reagent for the basicity or nucleophilicity of the DCC due to its pronounced acidity and suppresses base catalyzed side reactions, in particular racemization.

References

  1. ↑ Corey RB (July 1938). "Crystal Structure of Diketopiperazine". Journal of the American Chemical Society. 60 (7): 1598–1604. doi:10.1021/ja01274a023.
  2. 1 2 3 4 5 6 7 8 9 10 Borthwick AD (May 2012). "2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products". Chemical Reviews. 112 (7): 3641–3716. doi:10.1021/cr200398y. PMID   22575049.
  3. 1 2 Borthwick AD, Da Costa NC (2017). "2,5-Diketopiperazines in Food and Beverages: Taste and Bioactivity". Critical Reviews in Food Science and Nutrition. 57 (4): 718–742. doi:10.1080/10408398.2014.911142. PMID   25629623. S2CID   1334464.
  4. ↑ Shimoyama A, Ogasawara R (April 2002). "Dipeptides and diketopiperazines in the Yamato-791198 and Murchison carbonaceous chondrites". Origins of Life and Evolution of the Biosphere. 32 (2): 165–179. Bibcode:2002OLEB...32..165S. doi:10.1023/A:1016015319112. PMID   12185674. S2CID   21283306.
  5. 1 2 Minelli A, Bellezza I, Grottelli S, Galli F (Aug 2008). "Focus on cyclo (His-Pro): history and perspectives as antioxidant peptide". Amino Acids. 35 (2): 283–289. doi:10.1007/s00726-007-0629-6. PMID   18163175. S2CID   22563583.
  6. ↑ Prasad C (Dec 1995). "Bioactive cyclic dipeptides". Peptides. 16 (1): 151–164. doi:10.1016/0196-9781(94)00017-Z. PMID   7716068. S2CID   44314137.
  7. ↑ Cornacchia C, Cacciatore I, Baldassarre L, Mollica A, Feliciani F, Pinnen F (Jan 2012). "Diketopiperazines as neuroprotective agents". Mini Reviews in Medicinal Chemistry. 12 (1): 2–12. doi:10.2174/138955712798868959. PMID   22070690.
  8. 1 2 3 4 Ilaria B (2014). "Cyclic dipeptides: from bugs to brain". Trends in Molecular Medicine. 20 (10): 551–8. doi:10.1016/j.molmed.2014.08.003. PMID   25217340.
  9. ↑ Tullberg M, Grøtli M, Luthman K (July 2006). "Efficient synthesis of 2, 5-diketopiperazines using microwave assisted heating". Tetrahedron. 62 (31): 7484–7491. doi:10.1016/j.tet.2006.05.010.
  10. ↑ Dömling A (January 2006). "Recent developments in isocyanide based multicomponent reactions in applied chemistry". Chemical Reviews. 106 (1): 17–89. doi:10.1021/cr0505728. PMID   16402771.
  11. ↑ Rhoden CR, Rivera DG, Kreye O, Bauer AK, Westermann B, Wessjohann LA (October 2009). "Rapid Access to N-substituted diketopiperazines by one-pot Ugi-4CR/deprotection+ activation/cyclization (UDAC)". Journal of Combinatorial Chemistry. 11 (6): 1078–1082. doi:10.1021/cc900106u. PMID   19795905.
  12. ↑ Marcaccini S, Pepino R, Pozo MC (April 2001). "A facile synthesis of 2, 5-diketopiperazines based on isocyanide chemistry". Tetrahedron Letters. 42 (14): 2727–2728. doi:10.1016/S0040-4039(01)00232-5.
  13. ↑ Peng J, Clive DL (December 2008). "Asymmetric Synthesis of the ABC-Ring System of the Antitumor Antibiotic MPC1001". The Journal of Organic Chemistry. 74 (2): 513–519. doi:10.1021/jo802344t. PMID   19067592.
  14. ↑ Nagel U, Menzel H, Lednor PW, Beck W, Guyot A, Bartholin M (May 1981). "Versuche zur Rhodium (I)-katalysierten asymmetrischen Hydrierung von α-Acetamidozimtsäure mit monomeren und polymeren Aminophosphinen/Rhodium (I) Catalyzed Asymmetric Hydrogenation of α-Acetamido Cinnamic Acid with Monomeric and Polymeric Aminophosphines". Zeitschrift für Naturforschung B. 36 (5): 578–584. doi:10.1515/znb-1981-0510. S2CID   95022362.
  15. ↑ Chaignaud M, Gillaizeau I, Ouhamou N, Coudert G (August 2008). "New highlights in the synthesis and reactivity of 1, 4-dihydropyrazine derivatives". Tetrahedron. 64 (35): 8059–8066. doi:10.1016/j.tet.2008.06.080.
  16. ↑ Wirth T (1997). "New Strategies toα-Alkylatedα-Amino Acids". Angewandte Chemie International Edition in English. 36 (3): 225–227. doi:10.1002/anie.199702251.
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