- Mechanism of 2,5-dioxopiperazine formation
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The cyclization of H-Ala-Pro-NH2 to the 2,5-dioxopiperazine (DKP) has been Studied as a model for the spontaneous cleavage of the peptide bond with concomitant formation of 2,5-dioxopiperazine that can occur at the N-terminus of a polypeptide chain. The reaction involves pre-equilibrium attack of the N-terminal amino group on the carbonyl carbon of the second residue giving a zwitterionic intermediate, T(±) which is in acid-base equilibrium with various forms characterized by the different grades of protonation, T0, T+ and T-. The Bronsted plot for the base-catalysis and the pH-rate profile give pK(a) ~ 7 and ~ 13 for the equilibria T- + H+ ? T(±) + T(-) + H(+) ? T0 respectively. The reaction is subjects to general base and general acid cataysis on different steps. Departure of the amino group from T0 and T- by two parallel routes gives the product. The bifunctional acid catalyst HCO3- strongly increase the reaction rate and at high concentrations cause a of the rate-limiting step. At high pH, the overall reaction rate is limited by the trans - cis isomerization of the Ala-Pro peptide bond.
- Capasso, Sante,Vergara, Alessandro,Mazzarella, Lelio
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- Solvent effects on diketopiperazine formation from N-terminal peptide residues
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The kinetics of diketopiperazine formation from the peptide H-Ala-Pro-NH2 with the unprotected amino group in the form of its trifluoroacetate salt have been investigated in a large number of solvents, including aprotic and hydroxylic solvents. The first-order rate constant is considerably affected by the solvent properties, its value spanning more than three orders of magnitude. Moreover, alkylammonium carboxylate salts are efficient catalysts of the reaction. The correlation with Kamlet-Taft solvent parameters shows that the reaction rate is retarded by solvents with a high capacity to stabilise solutes that are charged or dipolar, and that are hydrogen donors and/or acceptors. Solvents with high cohesive energy density values significantly increase the reaction rate. These results are discussed in terms of a proton switch in the rate determining step and of solvation stabilisation of the initial state of the peptide and of the transition state of the rate-limiting step.
- Capasso, Sante,Mazzarella, Lelio
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- Cyclo(l-proline-l-serine) Dipeptide Suppresses Seed Borne Fungal Pathogens of Rice: Altered Cellular Membrane Integrity of Fungal Hyphae and Seed Quality Benefits
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Five proline-containing diketopiperazines (Pro-DKPs) produced by antagonistic microorganisms as secondary metabolites were selected and synthesized under laboratory conditions. Out of five synthesized Pro-DKPs, cyclo(l-Pro-l-Ser) (DKP-6) revealed the best inhibition of fungal pathogens (Fusarium verticillioides and Fusarium fujikuroi) of rice under in vitro conditions with effective doses lower than standard fungicide carbendazim. DKP-6 induced stress on the fungal cell membrane integrity, which was revealed by calcofluor white and propidium iodide assays, endorsed by ultra-microscopic details and soluble protein leakage assays. In vivo seed treatment of infested rice seeds with DKP-6 at 2000 μg/mL for 10 h of seed treatment inflicted best reduction in seed rot and seedling blight with respect to control and carbendazim. Significant enhancement in seedling quality parameters were also observed. The work presented the strong influence of cyclo(l-Pro-l-Ser) as a mycocidal seed treatment agent better than synthetic toxic fungicides for rice.
- Poonia, Baninderjit Kaur,Sidhu, Anjali,Sharma, Anju Bala
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p. 2160 - 2168
(2022/02/23)
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- Molecular capture and conformational change of diketopiperazines containing proline residues by epigallocatechin-3-O-gallate in water
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The addition of an aqueous solution of diketopiperazine cyclo(Pro-Xxx) (Xxx: amino acid residue) to an aqueous solution of (?)-epigallocatechin-3-O-gallate (EGCg) led to precipitation of the complex of EGCg and cyclo(Pro-Xxx). The molecular capture abilities of cyclo(Pro-Xxx) using EGCg were evaluated by the ratio of the amount of cyclo(Pro-Xxx) included in the precipitates of the complex with EGCg to that of the total cyclo(Pro-Xxx) used. Stronger hydrophobicity of the side chain of the amino acid residue of cyclo(Pro-Xxx) led to a higher molecular capture ability. Furthermore, the molecular capture ability decreased when the side chain of the amino acid residue had a hydrophilic hydroxyl group. When diketopiperazine cyclo(Pro-Xxx), excluding cyclo(D-Pro-L-Ala), was taken into the hydrophobic space formed by the three aromatic A, B, and B′ rings of EGCg, and formed a complex, their conformation was maintained in the hydrophobic space. Based on nuclear Overhauser effect (NOE) measurement, the 3-position methyl group of cyclo(D-Pro-L-Ala) in D2O was axial, whereas that of cyclo(L-Pro-L-Ala) was equatorial. When cyclo(D-Pro-L-Ala) was taken into the hydrophobic space of EGCg and formed a 2:2 complex, its 3-position methyl group changed from the axial position to the equatorial position due to steric hindrance by EGCg.
- Ishizu, Takashi,Tokunaga, Miku,Fukuda, Moeka,Matsumoto, Mana,Goromaru, Takeshi,Takemoto, Soushi
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p. 585 - 589
(2021/06/06)
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- Cyclols Revisited: Facile Synthesis of Medium-Sized Cyclic Peptides
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Medium-sized rings, particularly the corresponding cyclic peptides, are challenging synthetic targets. In the present study, we report an approach to medium-sized cyclic peptides through targeted formation and collapse of cyclol intermediates. This methodology operates on β-amino imides derived from 2,5-diketopiperazines and offers a straightforward transition from frequently examined scaffolds in drug discovery to a rarely visited class of medium-sized rings.
- Mendoza-Sanchez, Rodrigo,Corless, Victoria B.,Nguyen, Q. Nhu N.,Bergeron-Brlek, Milan,Frost, John,Adachi, Shinya,Tantillo, Dean J.,Yudin, Andrei K.
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supporting information
p. 13319 - 13322
(2017/10/05)
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- Asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopiperazines by using dynamic kinetic resolution of α-bromo tertiary acetamides
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A new and efficient method for the asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopiperazines has been developed. The dynamic kinetic resolution of L-amino-acid-derived α-bromo tertiary amides in the nucleophilic substitution reaction with p-anisi
- Baek, Jinho,Kang, Seock Yong,Im, Chan,Park, Yong Sun
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p. 2780 - 2789
(2014/05/06)
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- AGRICULTURAL CHEMICAL CONTAINING 2,5-DIKETOPIPERAZINE DERIVATIVE AS ACTIVE INGREDIENT
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Disclosed herein is an agricultural agent containing a 2,5-diketopiperazine derivative capable of controlling plant diseases and promoting plant growth or an agriculturally acceptable salt thereof as an active ingredient.
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Paragraph 0033
(2013/06/05)
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- A new benzotriazole-mediated stereoflexible gateway to hetero-2,5- diketopiperazines
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Open chain Cbz-L-aa1-L-Pro-Bt (Bt=benzotriazole) sequences were converted into either the corresponding trans- or cis-fused 2,5- diketopiperazines (DKPs) depending on the reaction conditions. Thermodynamic tandem cyclization/epimerization afforded selectively the corresponding trans-DKPs (69-75%). Complementarily, tandem deprotection/cyclization led to the cis-DKPs (65-72%). A representative set of proline-containing cis- and trans-DKPs has been prepared. A mechanistic investigation, based on chiral HPLC, kinetics, and computational studies enabled a rationalization of the results. Stereoflexible route to DKPs: A convenient, versatile, and flexible benzotriazole-mediated methodology for the synthesis of proline-containing hetero-2,5-diketopiperazines (DKPs) is reported. Depending on the reaction conditions, either cis- or trans-configured DKPs were obtained starting from the same inexpensive l,l-dipeptidoyl benzotriazole key intermediate (see scheme). Kinetics, chiral HPLC, and computational studies forged a background for mechanistic rationalization. Copyright
- Monbaliu, Jean-Christophe M.,Hansen, Finn K.,Beagle, Lucas K.,Panzner, Matthew J.,Steel, Peter J.,Todadze, Ekaterina,Stevens, Christian V.,Katritzky, Alan R.
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experimental part
p. 2632 - 2638
(2012/04/17)
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- Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists
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Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
- Moir, Elizabeth M.,Yoshiizumi, Kazuya,Cairns, Jim,Cowley, Phillip,Ferguson, Morag,Jeremiah, Fiona,Kiyoi, Takao,Morphy, Richard,Tierney, Jason,Wishart, Grant,York, Mark,Baker, James,Cottney, Jean E.,Houghton, Andrea K.,McPhail, Petula,Osprey, Andrew,Walker, Glenn,Adam, Julia M.
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scheme or table
p. 7327 - 7330
(2011/01/12)
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- An efficient green synthesis of proline-based cyclic dipeptides under water-mediated catalyst-free conditions
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l-Proline-based cyclic dipeptides were synthesized from N-Boc-protected dipeptide methyl esters under catalyst-free condition using water as a solvent. One-pot deprotection and cyclization have been used as the key steps, providing an efficient and environmentally friendly approach. Clean reaction conditions, easy isolation, and good yields of cyclic dipeptides are the salient features of the proposed methodology.
- Thajudeen, Habeebullah,Park, Kyungseok,Moon, Surk-Sik,Hong, In Seok
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scheme or table
p. 1303 - 1305
(2010/04/29)
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- Enantioselective Henry reaction catalyzed by C2-symmetric chiral diamine-copper(II) complex
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A copper(II) complex of C2-symmetric diamine has been proved to be an efficient catalyst for the enantioselective Henry reaction between nitroalkanes and various aldehydes to provide β-hydroxy nitroalkanes in high yields (up to 97%), moderate diastereoselectivities (up to 71:29) and excellent enantiomeric excesses (up to 96%). The chiral nitroaldol adduct obtained has been further converted into chiral aziridine in few steps.
- Selvakumar, Sermadurai,Sivasankaran, Dhanasekaran,Singh, Vinod K.
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supporting information; experimental part
p. 3156 - 3162
(2011/02/25)
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- Diastereoselective alkylation of a proline-derived bicyclic lactim ether
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N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis- and trans-9. The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis-9, sterically more-demanding alkyl halides resulted in cisltrans mixtures. Electrophiles bearing a π-system favored the trans-products 9. Some isolated cis- and tranx-lactim ethers 9 were converted to the corresponding diketopiperazines cis- and trans-10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystallography (Figs. 1-4).
- Hendea, Daniela,Laschat, Sabine,Baro, Angelika,Frey, Wolfgang
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p. 1894 - 1909
(2007/10/03)
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- Structures, sensory activity, and dose/response functions of 2,5-diketopiperazines in roasted cocoa nibs (Theobroma cacao)
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The taste compounds inducing the blood-like, metallic bitter taste sensation reported recently for a dichloromethane extract prepared from roasted cocoa nibs were identified as a series of 25 diketopiperazines by means of HPLC degustation, LC-MS/MS, and i
- Stark, Timo,Hofmann, Thomas
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p. 7222 - 7231
(2007/10/03)
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- Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: Potential conformational mimetics for cis-peptidyl prolinamides
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The synthesis of a new fused 1,2,5-triazepine-1,5-dione heterocycle, which is expected to mimic structural features of cis-peptldyl prolinamides, is described. The required parent heterocycle, corresponding to cis-glycy-(2S)-prolinamide, has been prepared in good yield by the cyclisation of N-(2-bromoacetylprolyl)-hydrazine which is itself generated in situ from the bromoacetyl proline methyl ester. Analogues corresponding to cis-(2R)-alanyl- and cis-(2S)-alanyl-(2S)-prolinamide have been similarly prepared from the appropriate N-(2-bromopropionyl)proline methyl esters and hydrazine hydrate where the cyclisation step, involving the displacement of bromide, has been shown to occur with inversion of configuration at C-2 of the propionyl moiety. Acylation at the N-3 position of the triazepine is equivalent to N-terminal acylation of the residue preceding the proline residue in cis-aminoacyl prolinamides. This has been achieved without incident using standard peptide coupling procedures. Extension at the 'C-terminal' has been achieved by preparing elaborated hydrazine precursors which are reacted with suitably activated esters of N-α-halogenoacylprolines, prior to cyclisation, to give the required fused triazepine dione. Thus it is possible to prepare constrained cis-peptidyl prolyl peptide mimetics of defined stereochemistry based upon this new triazepine dione in which all of the non-proline residues can be varied.
- Lenman, Morag M.,Lewis, Arwel,Gani, David
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p. 2297 - 2311
(2007/10/03)
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- Chemical Characterization of Diketopiperazines in Beer
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Diketopiperazines (DKPs) corresponding to cyclic dipeptides have been detected in a variety of natural products as well as in processed foods, beverages, and food and beverage ingredients. A series of seven proline-based diketopiperazines, namely, cyclo(Ala-Pro), cyclo(Val-Pro), cyclo(Ile-Pro), cyclo(Leu-Pro), cyclo(Met-Pro), cyclo(Phe-Pro), and cyclo(Pro-Pro), has now been identified in beer. A marketplace cross-section of five commercial beers was studied, involving products manufactured in different countries using distinctly different raw materials and brewing styles; maximum concentrations of individual diketopiperazines in various beers ranged from below detection limit to approximately 24 ppm. The flavor characteristics of these compounds were described variously as bitter, mouth coating, drying, astringent, salty, metallic, and grainy when evaluated in water at concentrations ranging from 10 to 50 ppm. However, it is questionable whether or not the diketopiperazines reported here make a significant contribution to either the aroma or taste of most beers.
- Gautschi, Markus,Schmid, Joachim P.,Peppard, Terry L.,Ryan, Thomas P.,Tuorto, Raymond M.,Yang, Xiaogen
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p. 3183 - 3189
(2007/10/03)
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- Synthesis and structure of cis-peptidyl prolinamide mimetics based upon 1,2,5-triazepine-3,6-diones
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The synthesis of novel constrained cis-peptidyl prolinamide mimetics for the dipeptide amides glycyl (2S)-prolinamide, (2S)-alanyl (2S)-prolinamide and (2R)-alanyl (2S)-prolinamide and some analogues, based upon fused 1,2,5-triazepine-3,6-diones, is described; these are suitable for elaboration into larger peptides at both the carboxy and amino termini, X-ray crystal structures for some of the compounds and intermediates are also presented.
- Lenman, Morag M.,Ingham, Scott L.,Gani, David
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- Prevention of Diketopiperazine Formation in Peptide Synthesis by a Simultaneous Deprotection-Coupling Procedure: Entrapment of Reactive Nucleophilic Species by in situ Acylation
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Hydrogenolysis of Z-amino acid-D-Pro-OMe dipeptides in the presence of acetic acid results, almost quantitatively, in the formation of diketopiperazines, whereas in the presence of Boc- or 2-(trimethylsilyl)ethoxycarbonyl protected amino acid pentafluorop
- Shute, Richard E.,Rich, Daniel H.
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p. 1155 - 1156
(2007/10/02)
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- Neighboring Residue Effects: Evidence for Intramolecular Assistance to Racemization or Epimerization of Dipeptide Residues
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Dipeptides, their methyl esters, diketopiperazines (DKP), and N-substituted derivatives were racemized at high temperatures (approximately 120 deg C) in aqueous phosphate buffered solutions at pH values close to pH of maximum racemization (approximately 8).The racemization of the dipeptides Ala-Gly and Gly-Ala followed reversible first-order kinetics.The initial rate of racemization of DKP was very fast but soon slowed down, supposedly due to hydrolysis.The resulting rate was similar to that of the dipeptides.Esters of dipeptides followed racemization patterns similar to DKP.The racemization rate constants of the dipeptides studied were shown to be independent of the concentration of the dipeptide and the concentration of buffer.A carboxy-terminal proline residue greatly increased the rate of racemization (epimerization) of the amino-terminal residue.Increasing the basicity of the N-terminal amino acid residue increased the rate of racemization (or epimerization) of the C-terminal residue unless the C-terminal was sterically hindered as the Ile and Val.Decreasing the basicity of the N-terminal amino acid residue decreased racemization or epimerization for nonhindered C-terminal amino acids.These results support the influence of neighboring groups in the racemization or epimerization of dipeptides.DKP formation is a competing reaction allowing racemization or epimerization in dipeptides.Dipeptide racemization or epimerization is proposed to be the result of combination of intramolecular base assistance and DKP formation.
- Smith, Grant Gill,Evans, Robert C.,Baum, Rocky
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p. 7327 - 7332
(2007/10/02)
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