- 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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- Unambiguous stereochemical assignment of cyclo(Phe-pro), cyclo(leu-pro), and cyclo(val-pro) by electronic circular dichroic spectroscopy
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2,5-diketopiperazines (DKPs) are cyclic dipeptides ubiquitously found in nature. In particular, cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) are frequently detected in many microbial cultures. Each of these DKPs has four possible stereoisomers due to the presence of two chirality centers. However, absolute configurations of natural DKPs are often ambiguous due to the lack of a simple, sensitive, and reproducible method for stereochemical assignment. This is an important problem because stereochemistry is a key determinant of biological activity. Here, we report a synthetic DKP library containing all stereoisomers of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro). The library was subjected to spectroscopic characterization using mass spectrometry, NMR, and electronic circular dichroism (ECD). It turned out that ECD can clearly differentiate DKP stereoisomers. Thus, our ECD dataset can serve as a reference for unambiguous stereochemical assignment of cyclo(Phe-Pro), cyclo(Leu-Pro), and cyclo(Val-Pro) samples from natural sources. The DKP library was also subjected to a biological screening using assays for E. coli growth and biofilm formation, which revealed distinct biological effects of cyclo(D-Phe-L-Pro).
- Dewan, Faizunnahar,Domzalski, Alison,Kawamura, Akira,Margent, Liliana,Pilarsetty, Naga Vara Kishore,Vigo, Valeria,Xu, Yujia
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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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- Antidiabetic in vitro and in vivo evaluation of cyclodipeptides isolated from Pseudomonas fluorescens IB-MR-66e
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Three cyclodipeptides [cyclo(l-Pro-l-Leu), 1; cyclo(l-Pro-l-Val), 2; and cyclo(l-Pro-l-Phe), 3] were isolated from Pseudomonas fluorescens IB-MR-66e. The structures were established by spectral means and corroborated by synthesis. The antidiabetic potential of compounds 1-3 was explored in vivo, in vitro and in silico. The three peptides showed important inhibitory activity against the α-glucosidase enzyme. Further analysis in vivo using a sucrose tolerance test corroborated that compounds 1 and 3 (1-30 mg kg-1) significantly reduced the postprandial state. Peptide 1 (1-30 mg kg-1) also reduced the postprandial peak after a glucose challenge and exhibited significant hypoglycemia during an insulin tolerance test; thus, its antidiabetic action involved also an improvement of insulin utilization not related to Akt phosphorylation nor to an increment in mitochondrial bioenergetics nor insulin secretion.
- Lozano-González,Ovalle-Magallanes,Rangel-Grimaldo,De La Torre-Zavala,Noriega,Tovar-Palacio,Tovar,Mata
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supporting information
p. 7756 - 7762
(2019/05/27)
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- Anti-biofilm and anti-adherence properties of novel cyclic dipeptides against oral pathogens
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Microorganisms embedded in a biofilm are significantly more resistant to antimicrobial agents and the defences of the human immune system, than their planktonic counterpart. Consequently, compounds that can inhibit biofilm formation are of great interest for novel therapeutics. In this study, a screening approach was used to identify novel cyclic dipeptides that have anti-biofilm activity against oral pathogens. Five new active compounds were identified that prevent biofilm formation by the cariogenic bacterium Streptococcus mutans and the pathogenic fungus Candida albicans. These compounds also inhibit the adherence of microorganisms to a hydroxylapatite surface. Further investigations were conducted on these compounds to establish the structure–activity relationship, and it was deduced that the common cleft pattern is required for these molecules to act effectively against biofilms.
- Simon, Ga?lle,Bérubé, Christopher,Voyer, Normand,Grenier, Daniel
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p. 2323 - 2331
(2018/12/11)
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- Interfacial supramolecular biomimetic epoxidation catalysed by cyclic dipeptides
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We synthesised a library of cis- and trans-cyclic dipeptides and evaluated their efficacy as catalysts in the asymmetric Weitz-Scheffer epoxidation of trans-chalcone. A thorough investigation relying on structure-activity studies and computational studies provided insights into the mechanism of the process. Our results revealed some structural features required for efficient conversion and for introduction of chirality into the product. The cyclic dipeptide acts as a catalyst by templating a supramolecular arrangement at the aqueous-organic interface required for efficient transformations to occur. Among all cyclic dipeptides investigated, cyclo(Leu-Leu) was the most efficient supramolecular catalyst.
- Bérubé, Christopher,Barbeau, Xavier,Cardinal, Sébastien,Boudreault, Pierre-Luc,Bouchard, Corinne,Delcey, Nicolas,Lagüe, Patrick,Voyer, Normand
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p. 330 - 349
(2017/03/15)
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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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- Cyclic dipeptides exhibit potency for scavenging radicals
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Twenty kinds of cyclic dipeptides containing l-leucine were synthesized, and their antioxidant activity against .OH and O2·- was investigated. Compounds possessing polar amino acid residues, such as Asp, Cys, Glu, Lys, Pro, Ser, and Trp, exhibited higher antioxidant activity against .OH than vitamin E. However, only cyclo(l-Cys-l-Leu) scavenged O2·-.
- Furukawa, Tadashi,Akutagawa, Takashi,Funatani, Hitomi,Uchida, Toshikazu,Hotta, Yoshihiro,Niwa, Masatake,Takaya, Yoshiaki
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p. 2002 - 2009
(2012/05/04)
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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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- 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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- 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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- 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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- Synthesis of diketopiperazines containing prolinyl unit - Cyclo(L-prolinyl-L-leucine), cyclo(L-prolinyl-L-isoleucine) and cyclo(L-tryptophyl-L-proline)
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Diketopiperazines cyclo(L-prolinyl-L-isoleucine) 4a, cyclo(L-prolinyl-L-leucine) 4b and cyclo(L-tryptophyl-L-proline) 6 were prepared from their respective suitably protected amino acid derivatives by standard peptide chemistry. Cyclo(L-(4-hydroxyprolinyl)-L-phenylalanine) 3, 4a and cyclo(L-prolinyl-L-tyrosine) 5 were tested for their antibacterial activity.
- Jhaumeer-Laulloo,Khodabocus,Jugoo,Jheengut,Sobha
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p. 765 - 768
(2007/10/03)
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- Unexpected Hydrogenation of C-C-Double Bonds with tert-Butyl Iodide
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Heating of 3-isobutylidene-2,5-diketopiperazines 1 or 4, maleinimide or 2,3-dichloro-5,6-dicyano-p-benzoquinone with tert-butyl iodide in toluene gave rise to hydrogenation of the conjugated C-C-double bond affording 3-isobutyldiketopiperazines 2(rac) and 3(rac), succinimide, or 2,3-dichloro-5,6-dicyanohydroquinone, respectively. Furthermore, an interesting N-O-migration of a benzoyl group as well as reductive aromatization to pyrazines 5 and 6, respectively, were observed.
- Jin, Shangde,Liebscher, Juergen
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p. 390 - 392
(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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- Total Synthesis of Thymosin β4, 2. Conventional Synthesis of the Fragment of Thymosin β4
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As part of the total synthesis of thymosin β4 three synthetic pathways for the synthesis of the thymosin β4 fragment are described.The side-chain functions are protected by tert-butyl and the α-amino residues by Z groups.As temporary protection of the carboxyl function the phenyl ester is successfully used.Key Words: Thymosin β4, fragment /Thymus peptides/Amino acids/Protecting groups, phenyl esters of peptides as/Peptides
- Kapurniotu, Afroditi,Voelter, Wolfgang
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p. 361 - 370
(2007/10/02)
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- From N-Nitroacetylproline to Leucylproline
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The potential of the nitroacetyl group in peptide synthesis has been demonstrated by converting N-nitroacetylproline ethyl ester into cyclo(L-Leu-L-Pro).
- Manjunatha, Sulur G.,Rajappa, Srinivasachari
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p. 372 - 373
(2007/10/02)
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- Model studies of competing hydrolysis and epimerization of some tetrapeptides of interest in amino acid racemization studies in geochronology
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The processes of epimerization of individual peptide units in proteins and the concurrent cleavage of peptide bonds are modelled by heating some tetrapeptide and tetrapeptide derivatives to 148.5 deg C in pH 6.8 phosphate buffer.An excess of D-proline was observed during the heating of L-propyl-L-leucylglycylglycine.The D/L ratio of proline attains a maximum value of 2.1 after 90 minutes.The excess D-proline is attributed to the formation of a 2.3:1 mixture of diketopiperazines cyclo-(D-propyl-L-leucyl) and cyclo-(L-prolyl-L-leucyl).These two species account for most of the leucine and proline in the final mixture after the tetrapeptide is no longer detectable.Only small amounts of prolylleucine can be detcected after 50 hours.It is suggested that the above tetrapeptide undergoes internal aminolysis.Leucine in the tetrapeptide glycyl-L-leucylglycylglycine racemizes three times faster than in L-propyl-L-leucylglycylglycine.This demonstrates that an amino acid residue in a peptide chain does have an effect upon the rate of epimerization of a neighbouring peptide residue.A discussion of the geochemical implications of the results is included.
- Moir, Michael E.,Crawford, Robert J.
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p. 2903 - 2913
(2007/10/02)
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- Metabolites from the Marine Sponge Tedania ignis. A New Atisanediol and Several Known Diketopiperazines
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A new hydroxylated atisane, atisane-3β,16α-diol (5), has been isolated from the Caribbean sponge Tedania ignis, and its structure has been determined by single-crystal X-ray diffraction.The absolute configuration was assigned from circular dichroism data for the derived ketone 6.Also identified in the extracts were batyl and chimyl alcohol, the diketopiperazines cyclo-(L-Pro-L-Leu) (1), cyclo-(L-Pro-L-Val) (2), and cyclo-(Pro-Ala) (3), and epiloliolide (4).
- Schmitz, Francis J.,Vanderah, David J.,Hollenbeak, Keith H.,Enwall, Carol E.L.,Gopichand, Yalamanchili,et al.
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p. 3941 - 3945
(2007/10/02)
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