- A reaction network for triglycine synthesis under hydrothermal conditions
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It has been hypothesized that chemical evolution leading to the origin of life might have occurred in hydrothermal environments on primitive Earth. To examine this hypothesis, we investigated how the polymerization of amino acids proceeds under high-temperature and high-pressure conditions. We investigated a reaction network consisting of glycine and oligoglycines up to trimer, and the condensation/hydrolysis reactions among these molecules. We determined the rate constants of these reactions in experiments employing a flow reactor at 200 °C and 25 MPa. We found that two condensation reactions of glycine, which yield diglycine and diketopiperazine as products, have larger equilibrium constants under these conditions than at 25 °C. This result supports the hypothesis that hydrothermal conditions are thermodynamically favorable for chemical evolution. We also found that triglycine formation is mediated by diketopiperazine at 200 °C and 25 MPa. This implies that diketopiperazine acts as an important intermediate in the polymerization process of amino acids, which might have occurred in hydrothermal environments on primitive Earth.
- Mitsuzawa, Shigenobu,Yukawa, Tetsuyuki
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- Osmium(VIII)-catalyzed oxidation of some cyclic amines by potassium hexacyanoferrate(III) in alkaline media: A kinetics and mechanistic study
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Reactions of morpholine, piperidine, and piperazine with Os(VIII) -catalyzed hexacyanoferrate(III) in alkaline media to produce the corresponding lactam have been studied at constant temperature and ionic strength. The reactions followed first-order kinetics with respect to [amine] and [Os(VIII)] but were independent of [Fe(CN)63-] and [OH-]. The effects of introduced electrolytes, potassium hexacyanoferrate(II), relative permitivity, and temperature have also been studied. A mechanism accounting for these results has been proposed.
- Al-Subu,Jondi,Amer,Hannoun,Musmar
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- Robustness, Entrainment, and Hybridization in Dissipative Molecular Networks, and the Origin of Life
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How simple chemical reactions self-assembled into complex, robust networks at the origin of life is unknown. This general problem-self-assembly of dissipative molecular networks-is also important in understanding the growth of complexity from simplicity in molecular and biomolecular systems. Here, we describe how heterogeneity in the composition of a small network of oscillatory organic reactions can sustain (rather than stop) these oscillations, when homogeneity in their composition does not. Specifically, multiple reactants in an amide-forming network sustain oscillation when the environment (here, the space velocity) changes, while homogeneous networks-those with fewer reactants-do not. Remarkably, a mixture of two reactants of different structure-neither of which produces oscillations individually-oscillates when combined. These results demonstrate that molecular heterogeneity present in mixtures of reactants can promote rather than suppress complex behaviors.
- Cafferty, Brian J.,Wong, Albert S. Y.,Semenov, Sergey N.,Belding, Lee,Gmür, Samira,Huck, Wilhelm T. S.,Whitesides, George M.
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- Addition reaction of 1,4-Dibromo-2,5-piperazinedione with 3,4-dihydro-2H-pyran
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Reaction of 1,4-dibromo-2,5-piperazinedione (1) with 3,4-dihydro-2H-pyran (2) under irradiation gave 1:1- and 1:2-addition products (3,4) and corresponding secondary products (5-7).The adducts were considered to be produced separately by photoinduced free radical addition as well as concomitant ionic addition reactions.
- Itoh, Kuniaki,Sera, Akira
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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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- Selective formation of glycylglycine by dehydration of glycine adsorbed on silica gel
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Silica gel promotes the selective dehydration of glycine to form intermediate glycylglycine, with inhibition of the formation of stable glycine anhydride and polymer products. IR measurements indicate that glycine adsorbed on silica gel results in the formation of neutral species having C=O and NH2 groups. The species is considered to stimulate dehydration, leading to the reported selective dehydration. Copyright
- Ogawa, Haruo,Fujigaki, Tamiki,Chihara, Teiji
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- Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s
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The synthesis and degradation mechanisms of a class of pH-sensitive, rapidly degrading cationic poly(α-aminoester)s are described. These reactive, cationic polymers are stable at low pH in water, but undergo a fast and selective degradation at higher pH to liberate neutral diketopiperazines. Related materials incorporating oligo(α-amino ester)s have been shown to be effective gene delivery agents, as the charge-altering degradative behavior facilitates the delivery and release of mRNA and other nucleic acids in vitro and in vivo. Herein, we report detailed studies of the structural and environmental factors that lead to these rapid and selective degradation processes in aqueous buffers. At neutral pH, poly(α-aminoester)s derived from N-hydroxyethylglycine degrade selectively by a mechanism involving sequential 1,5- A nd 1,6-O→N acyl shifts to generate bis(N-hydroxyethyl) diketopiperazine. A family of structurally related cationic poly(aminoester)s was generated to study the structural influences on the degradation mechanism, product distribution, and pH dependence of the rate of degradation. The kinetics and mechanism of the pH-induced degradations were investigated by 1H NMR, model reactions, and kinetic simulations. These results indicate that polyesters bearing α-ammonium groups and appropriately positioned N-hydroxyethyl substituents are readily cleaved (by intramolecular attack) or hydrolyzed, representing dynamic dual function materials that are initially polycationic and transform with changing environment to neutral products.
- Blake, Timothy R.,Ho, Wilson C.,Huttner, Melanie A.,Turlington, Christopher R.,Waymouth, Robert M.,Wender, Paul A.,Zang, Xiaoyu
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- Superactivity of MOF-808 toward Peptide Bond Hydrolysis
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MOF-808, a Zr(IV)-based metal-organic framework, has been proven to be a very effective heterogeneous catalyst for the hydrolysis of the peptide bond in a wide range of peptides and in hen egg white lysozyme protein. The kinetic experiments with a series of Gly-X dipeptides with varying nature of amino acid side chain have shown that MOF-808 exhibits selectivity depending on the size and chemical nature of the X side chain. Dipeptides with smaller or hydrophilic residues were hydrolyzed faster than those with bulky and hydrophobic residues that lack electron rich functionalities which could engage in favorable intermolecular interactions with the btc linkers. Detailed kinetic studies performed by 1H NMR spectroscopy revealed that the rate of glycylglycine (Gly-Gly) hydrolysis at pD 7.4 and 60 °C was 2.69 × 10-4 s-1 (t1/2 = 0.72 h), which is more than 4 orders of magnitude faster compared to the uncatalyzed reaction. Importantly, MOF-808 can be recycled several times without significantly compromising the catalytic activity. A detailed quantum-chemical study combined with experimental data allowed to unravel the role of the {Zr6O8} core of MOF-808 in accelerating Gly-Gly hydrolysis. A mechanism for the hydrolysis of Gly-Gly by MOF-808 is proposed in which Gly-Gly binds to two Zr(IV) centers of the {Zr6O8} core via the oxygen atom of the amide group and the N-terminus. The activity of MOF-808 was also demonstrated toward the hydrolysis of hen egg white lysozyme, a protein consisting of 129 amino acids. Selective fragmentation of the protein was observed with 55% yield after 25 h under physiological pH.
- Ly, Hong Giang T.,Fu, Guangxia,Kondinski, Aleksandar,Bueken, Bart,De Vos, Dirk,Parac-Vogt, Tatjana N.
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- Glycine homopeptides: The effect of the chain length on the crystal structure and solid state reactivity
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A series of linear oligoglycines has been studied using X-ray diffraction, thermal analysis complemented with simultaneous FTIR spectroscopy, gas chromatography-mass spectrometry analysis, and 1H/13C NMR. The new and previously reported data are rationalized to reveal the effect of the chain size on the crystal structure, molecular conformation and thermal stability of the oligopeptides in the solid state, as well as thermally induced transformations (pyrolysis) in the solid state and the gaseous phase. Tetraglycine (4G) and pentaglycine (5G) form triclinic crystals, P1, where they adopt a zwitterionic form and fully extended chain conformation. The antiparallel β sheet arrangement is similar to that in β-triglycine (β3G) and α-diglycine (α2G) but differs from the Form I of polyglycine (polyG). The stability sequence α2G 2O(gas) is endothermic with ΔH = 63.7(4) kJ mol-1 at 492 K. The standard enthalpy of the reaction α2G(solid) = c2G(solid) + H2O(liquid) was estimated to be ΔH298 ≈ 18 kJ mol-1 meaning the reaction is thermodynamically unfavorable under ambient conditions. Finally, the cyclization reaction mechanisms are discussed for the whole series studied. This journal is the Partner Organisations 2014.
- Smith, Aaron J.,Ali, Farukh I.,Soldatov, Dmitriy V.
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- PHOTOINDUCED ADDITION REACTION OF 1,4-DIBROMO-2,5-PIPERAZINEDIONE WITH 1-ALKENES.
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Irradiation of 1,4-dibromo-2,5-piperazinedione with olefins in acetonitrile gave mixtures of addition products (1:1-adducts and 1:2-adducts). Addition of 1,2-epoxybutane (a hydrogen bromide scavenger) resulted in enhanced yields of the adducts. Structures of the adducts were elucidated and a reaction mechanism is discussed.
- Itoh,Yamada,Sera
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- Spectroscopy of hydrothermal reactions. 27. Simultaneous determination of hydrolysis rate constants of glycylglycine to glycine and glycylglycine-diketopiperazine equilibrium constants at 310-330°C and 275 bar
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Hydrolysis rate constants of glycylglycine to glycine and equilibrium constants between glycylglycine and diketopiperazine were determined simultaneously in situ using an FT-IR spectroscopy flow reactor at 310-330°C and 275 bar. The hydrolysis of the peptide bond in neutral hydrothermal solution follows the first-order (or pseudo-first-order) rate law. The cyclization of dipeptides is very prominent at high temperatures. Pressure affects the hydrolysis rate and the enthalpy of cyclization of the dipeptide. Specifically, the activation energy for hydrolysis of the dipeptide is reduced by about 50 kJ/mol and the standard enthalpy change of cyclization of the dipeptide is increased by about 50 kJ/mol when pressure is increased from a stream pressure of 1-16 bar to a solution pressure of 275 bar. The data analysis method used in this work is general and could be applied to other dipeptides provided the decomposition rate of the free amino acid product of hydrolysis is monitored.
- Li, Jun,Brill, Thomas B.
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- Substitution of halogen atom in α-halonitro compounds of the aliphatic series 6. Preparation and reduction of alkyl α-halo- and α-sulfosubstituted α-nitrocarboxylates
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Ethyl α-halo-α-nitropropionate and -butyrate were prepared by alkylating ammonium salts of ethyl bromo- and chloronitroacetates.The addition of alkyl acrylates to alkyl chloronitroacetates or their salts gives dialkyl α-chloro-α-nitroglutarates.Sodium salts of ethyl α-nitro-α-sulfo-β-hydroxypropionate and -butyrate were obtained by the sulfodehalogenation of ethyl α-chloro-α-nitro-β-hydroxypropionate and -butyrate with sodium dithionite.Esters of α-amino acid hydrochlorides were prepared by the reduction of alkyl α-chloro-α-nitrocarboxylates.The hydrogenation of alkyl nitrosulfoacetates leads to the corresponding disodium salts of alkyl aminodisulfoacetates and piperazine-2,5-dione. - Key words: halonitrocarboxylates, alkylation, Michael reaction, sulfodehalogenation, catalytic hydrogenation; amino acids; alkyl aminodisulfoacetates.
- Yurtanov, A. I.,Baidildaeva, S. K.,Chekhlov, A. N.,Zefirov, N. S.
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- Comparative study of the reactivity of zirconium(IV)-substituted polyoxometalates towards the hydrolysis of oligopeptides
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The hydrolytic activity of the ZrIV-substituted Keggin-type (Et2NH2)8[{α-PW11O39Zr-(μ-OH)(H2O)}2]·7H2O (1), Lindqvist-type (Me4N)2[W5O18Zr(H2O)3] (2), and Wells-Dawson-type Na14[Zr4(P2W16O59)2(μ3-O)2(OH)2(H2O)4]·57H2O (3) polyoxometalates (POMs) towards the peptide bonds in the oligopeptides triglycine, tetraglycine, glycylglycylhistidine, and glycylserylphenylalanine was investigated by kinetic methods and multinuclear NMR spectroscopy. 31P NMR and UV/Vis spectroscopy showed that 1-3 were stable under the conditions used to study peptide bond hydrolysis. The reactivity of 1-3 towards oligopeptides was compared on the basis of the amount of free glycine produced at a certain time increment. In the presence of 1-3, rate constants in the range 6.25×10-7 to 10.14×10-7 s-1 were obtained, whereas no hydrolysis was observed after one month in the absence of these POMs. The results showed that the Keggin-type complex 1 was the most active towards peptide bond hydrolysis in tri- and tetrapeptides. 1H and 13C NMR spectroscopy showed that triglycine, tetraglycine, and glycylserylphenylalanine interact with 1 and 2 preferentially through the amine nitrogen atom and the N-terminal amide oxygen atom to activate the peptide bond towards hydrolysis. The coordination of glycylglycylhistidine resulted in multiple complexes with 1-3 as a result of additional imidazole coordination to the ZrIV centers.
- Ly, Hong Giang T.,Absillis, Gregory,Parac-Vogt, Tatjana N.
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- Investigation of permeation of theophylline through skin using selected piperazine-2,5-diones
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Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 ?C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.
- Pokorna, Aneta,Bobal, Pavel,Oravec, Michal,Rarova, Lucie,Bobalova, Janette,Jampilek, Josef
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- Cyclic dipeptides: Catalyst/promoter-free, rapid and environmentally benign cyclization of free amino acids
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"The best catalyst is no catalyst." With growing public concern over global warming and the amount of greenhouse gases, it is important to reduce the amount of chemicals and eliminate waste, to obtain better results in a simple, selective, safe, and environmentally benign fashion compared to conventional tedious chemical synthesis. Herein, we disclose an environmentally benign, rapid, catalyst/promoter/coupling reagent-free cyclization procedure of free amino acids to furnish exclusively cyclic dipeptides (2,5- diketopiperazines, DKPs) in excellent or even quantitative yield, along with their solid state self-assembling properties. This process is extremely simple and highly efficient with little or no traditional synthetic skills and without any chromatographic purification. Synthesis of structurally diverse DKPs has been achieved with a dramatic decrease in the reaction time, the amount/number of solvents used, a significant increase in the yield and nearly complete elimination of waste. As a result, this is an excellent example for the environmentally benign, clean and green chemistry concept. The most exciting outcome of our investigation is an unusual case of chiral self-recognition encountered upon the cyclization of rac-pipecolic acid, which resulted in the formation of the meso-product exclusively.
- Nonappa,Ahonen, Kari,Lahtinen, Manu,Kolehmainen, Erkki
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- Rates of uncatalyzed peptide bond hydrolysis in neutral solution and the transition state affinities of proteases
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To assess the relative proficiencies of enzymes that catalyze the hydrolysis of internal and C-terminal peptide bonds, the rates of the corresponding nonenzymatic reactions were examined at elevated temperatures in sealed quartz tubes, yielding linear Arrhenius plots. The results indicate that in neutral solution at 25°C, peptide bonds are hydrolyzed with half-times of approximately 500 years for the C-terminal bond of acetylglycylglycine, 600 years for the internal peptide bond of acetylglycylglycine N-methylamide, and 350 years for the dipeptide glycylglycine. These reactions, insensitive to changing pH or ionic strength, appear to represent uncatalyzed attack by water on the peptide bond. Comparison of rate constants indicates very strong binding of the altered substrate in the transition states for the corresponding enzyme reactions, K(tx) attaining a value of less than 10-17 M in carboxypeptidase B. The half-life of the N-terminal peptide bond in glycylglycine N-methylamide, whose hydrolysis might have provided a reference for assessing the catalytic proficiency of an aminopeptidase, could not be determined because this compound undergoes relatively rapid intramolecular displacement to form diketopiperazine (t( 1/4 ) ~ 35 days at pH 7 and 37°C). The speed of this latter process suggests an evolutionary rationale for posttranslational N-acetylation of proteins in higher organisms, as a protection against rapid degradation.
- Radzicka,Wolfenden
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- Participation of aromatic side chains in diketopiperazine ensembles
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This study probes the beneficial role of aromatic side chains in peptide self-assembly by choosing four diketopiperazine model systems variably composed of glycine, proline, phenylalanine, and tryptophan residues.
- Joshi,Verma, Sandeep
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- Mechanochemical Prebiotic Peptide Bond Formation**
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The presence of amino acids on the prebiotic Earth, either stemming from endogenous chemical routes or delivered by meteorites, is consensually accepted. Prebiotically plausible pathways to peptides from inactivated amino acids are still unclear as most oligomerization approaches rely on thermodynamically disfavored reactions in solution. Now, a combination of prebiotically plausible minerals and mechanochemical activation enables the oligomerization of glycine at ambient temperature in the absence of water. Raising the reaction temperature increases the degree of oligomerization concomitantly with the formation of a commonly unwanted cyclic glycine dimer (DKP). However, DKP is a productive intermediate in the mechanochemical oligomerization of glycine. The findings of this research show that mechanochemical peptide bond formation is a dynamic process that provides alternative routes towards oligopeptides and establishes new synthetic approaches for prebiotic chemistry.
- Cindro, Nikola,Grube?i?, Sa?a,Hernández, José G.,Me?trovi?, Ernest,Stolar, Tomislav,U?arevi?, Krunoslav
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- Preparation, characterization, and release of amoxicillin from electrospun fibrous wound dressing patches
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Purpose: To produce electrospun polymeric fibrous wound dressing patches that can release the antibiotic drug amoxicillin in a controlled manner. Methods: Poly(D,L-lactide-co-glycolide) acid (PLGA) fibrous dressings with entrapped amoxicillin were produced by electrospinning. The morphology and successful entrapment of amoxicillin in the PLGA fibrous dressings were validated by scanning electron microscopy (SEM) and Fourier Transform Infrared (FTIR) spectroscopy. The rate of drug release from the dressing patches was measured in various media for a period of 21 days using UV spectroscopy. Results: PLGA fibres entrapping amoxicillin were collected for 300 s and then cut to form square patches with an average weight of 55 mg. Each dressing patch contained ~2 mg of amoxicillin. The mean fibre diameter was 2.2 ± 0.4 μm. The drug release from the PLGA dressings was found to be different for each medium during the 21-day release period with the highest and lowest concentration of drug released observed when the dressings were immersed in simulated body fluid (SBF) and phosphate buffered saline (PBS), respectively. Conclusions: The release profiles obtained in this study and the well-established biocompatibility of PLGA indicate that the fibre-based patches with entrapped amoxicillin fabricated in this work are very well suited for applications in wound healing and infection control.
- Sofokleous, Panagiotis,Stride, Eleanor,Edirisinghe, Mohan
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- Oligomerization of glycine and alanine on metal(II) octacynaomolybdate(IV): Role of double metal cyanides in prebiotic chemistry
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Condensation reactions of amino acid (glycine and alanine) on the surface of metal(II) octacyanomolybdate( IV) (MOCMo) complexes are investigated using highperformance liquid chromatography (HPLC) and electron spray ionizations-mass spectroscopy (ESI-MS). The series of MOCMo have been synthesized and the effect of outer sphere metal ions present in the MOCMo on the oligomerization of glycine and alanine at different temperature and time found out. Formation of peptides was observed to start after 7 days at 60°C. Maximum yield of peptides was found after 35 days at 90°C. It has been found that zinc(II) octacyanomolybdate( IV) and cobalt(II) were the most effective metal cations present in outer sphere of the MOCMo for the production of high yield of oligomerized products. Surface area of MOCMo seems to play dominating parameter for the oligomerization of alanine and glycine. The results of the present study reveal the role of MOCMo in chemical evolution for the oligomerization of biomolecules. Springer-Verlag 2012.
- Kumar, Anand,Kamaluddin
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- [11C]Glycylsarcosine: Synthesis and in vivo evaluation as a PET tracer of PepT2 transporter function in kidney of PepT2 null and wild-type mice
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[11C]Glycylsarcosine (Gly-Sar) was synthesized as a potential radiotracer to investigate the localization and in vivo function of the peptide transporter PepT2 in mouse kidney. Its C-11 labeled diketopiperazine derivative, [11C]cyclo(Gly-Sar) [1-methylpiperazine-2,5-dione], was also evaluated as a potential tracer. [11C]Gly-Sar exhibited rapid initial uptake into kidneys with slow clearance from the medulla, consistent with uptake and retention of the radiotracer through the actions of PepT2. In contrast, the corresponding cyclized dipeptide [11C]cyclo(Gly-Sar) showed rapid clearance and accumulation only in the renal pelvis region. Involvement of PepT2 in reabsorption and delayed clearance of [ 11C]Gly-Sar was confirmed using the PepT2 knockout mouse, where rapid renal elimination of [11C]Gly-Sar and the absence of radioactivity in medulla were observed. This study demonstrates using in vivo imaging technique that PepT2 is primarily responsible for renal tubular active reabsorption of Gly-Sar, and provides a new tool for studying tubular peptide reabsorption and clearance.
- Nabulsi, Nabeel B.,Smith, David E.,Kilbourn, Michael R.
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- THE "GAS-SOLID-PHASE" 2,5-DIOXOPIPERAZINE SYNTHESIS. CYCLIZATION OF VAPOROUS DIPEPTIDES ON SILICA SURFACE
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The "gas-solid-phase" method is used for the preparation of both symmetric and asymmetric 2,5-dioxopiperazines via cyclization of vaporous linear dipeptides in the presence of silica.
- Basiuk, Vladimir,Gromovoy, Taras Yu.
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- Three-component catalytic method for synthesis of α-amino phosphonates with the use of α-amino acids as amine component
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Interaction of aliphatic and aromatic aldehydes and ketones with optically active L-α-amino acids or their esters in the three-component catalytic one-pot synthesis of α-aminophosphonates was studied. The corresponding α-amino phosphonates are formed in high yields as mixtures of diastereomers.
- Matveeva,Podrugina,Prisyazhnoi,Rusetskaya,Zefirov
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- A novel approach to the synthesis of symmetric optically active 2,5-dioxopiperazines
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'Gas-solid-phase' method for the preparation of some cyclic dipeptides,2,5-dioxopiperazines (diketopiperazines), is described. The method implies cyclodimerization of vaporous aliphatic α-amino acids in the presence of silica at reduced pressure and yields optically active 2,5-dioxopiperazines.
- Basiuk,Gromovoy,Chuiko,Soloshonok,Kukhar
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- Reaction of amino acids in a supercritical water-flow reactor simulating submarine hydrothermal systems
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A novel supercritical water flow-reactor was constructed in order to simulate submarine hydrothermal systems. The temperature of fluid inside the reaction tube could be monitored with thermocouples, which was proved to be different from the temperature outside the reaction tube. Oligomers of glycine up to tetraglycine were formed when a 100 mM glycine solution was heated at 200-350 °C for 2 minutes. None of glycine peptides were produced at 400 °C. It was suggested, however, that the formation of glycine condensates at higher temperature, including supercritical conditions of water. The stability of some amino acids under hydrothermal conditions was examined. ω-Amino acids and glutamic acid, which can form intramolecular condensates, showed higher stability than other α-amino acids at higher temperature, including supercritical conditions.
- Islam, Md. Nazrul,Kaneko, Takeo,Kobayashi, Kensei
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- En Route to a Heterogeneous Catalytic Direct Peptide Bond Formation by Zr-Based Metal-Organic Framework Catalysts
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Peptide bond formation is a challenging, environmentally and economically demanding transformation. Catalysis is key to circumvent current bottlenecks. To date, many homogeneous catalysts able to provide synthetically useful methods have been developed, while heterogeneous catalysts remain largely restricted to the studies addressing the prebiotic formation of peptides. Here, the catalytic activity of Zr6-based metal-organic frameworks (Zr-MOFs) toward peptide bond formation is investigated using dipeptide cyclization as a model reaction. Unlike previous catalysts, Zr-MOFs largely tolerate water, and reactions are carried out under ambient conditions. Notably, the catalyst is recyclable and no additives to activate the COOH group are necessary, which are common limitations of previous methods. In addition, a broad reaction scope tolerates substrates with bulky and Lewis basic groups. The reaction mechanism was assessed by detailed mechanistic and computational studies and features a Lewis acid activation of carboxylate groups by Zr centers toward amine addition in which an alkoxy ligand on adjacent Zr sites assists in lowering the barrier of key proton transfers. The proposed concepts were also used to study the formation of intermolecular peptide bond formation. While intrinsic challenges associated with the catalyst structure and water removal limit a more general intermolecular reaction scope under current conditions, the results suggest that further design of Zr-MOF catalysts could render these materials broadly useful as heterogeneous catalysts for this challenging transformation.
- Conic, Dragan,De Azambuja, Francisco,Harvey, Jeremy N.,Loosen, Alexandra,Parac-Vogt, Tatjana N.,Van Den Besselaar, Maxime
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p. 7647 - 7658
(2021/06/30)
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- Enantioselective Synthesis of Chiral Substituted 2,4-Diketoimidazolidines and 2,5-Diketopiperazines via Asymmetric Hydrogenation
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An enantioselective hydrogenation of 5-alkylidene-2,4-diketoimidazolidines (hydantoins) and 3-alkylidene-2,5-ketopiperazines catalyzed by the Rh/f-spiroPhos complex under mild conditions has been developed, which provides an efficient approach to the highly enantioselective synthesis of chiral hydantoins and 2,5-ketopiperazine derivatives with high enantioselectivities up to 99.9% ee.
- Xiao, Guiying,Xu, Shuang,Xie, Chaochao,Zi, Guofu,Ye, Weiping,Zhou, Zhangtao,Hou, Guohua,Zhang, Zhanbin
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supporting information
p. 5734 - 5738
(2021/08/01)
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- Interplay between structural parameters and reactivity of Zr6-based MOFs as artificial proteases
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Structural parameters influencing the reactivity of metal-organic frameworks (MOF) are challenging to establish. However, understanding their effect is crucial to further develop their catalytic potential. Here, we uncovered a correlation between reaction kinetics and the morphological structure of MOF-nanozymes using the hydrolysis of a dipeptide under physiological pH as model reaction. Comparison of the activation parameters in the presence of NU-1000 with those observed with MOF-808 revealed the reaction outcome is largely governed by the Zr6 cluster. Additionally, its structural environment completely changes the energy profile of the hydrolysis step, resulting in a higher energy barrier ΔG? for NU-1000 due to a much larger ΔS? term. The reactivity of NU-1000 towards a hen egg white lysozyme protein under physiological pH was also evaluated, and the results pointed to a selective cleavage at only 3 peptide bonds. This showcases the potential of Zr-MOFs to be developed into heterogeneous catalysts for non-enzymatic but selective transformation of biomolecules, which are crucial for many modern applications in biotechnology and proteomics.
- De Azambuja, Francisco,De Vos, Dirk,Loosen, Alexandra,Moons, Jens,Parac-Vogt, Tatjana N.,Simms, Charlotte,Smolders, Simon
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p. 6662 - 6669
(2020/07/23)
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- Water-Tolerant and Atom Economical Amide Bond Formation by Metal-Substituted Polyoxometalate Catalysts
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A simple, safe, and inexpensive amide bond formation directly from nonactivated carboxylic acids and free amines is presented in this work. Readily available Zr(IV)- and Hf(IV)-substituted polyoxometalates (POM) are shown to be catalysts for the amide bond formation reaction under mild conditions, low catalyst loading, and without the use of water scavengers, dry solvents, additives for facilitating the amine attack, or specialized experimental setups commonly employed to remove water. Detailed mechanistic investigations revealed the key role of POM scaffolds which act as inorganic ligands to protect Zr(IV) and Hf(IV) Lewis acidic metals against hydrolysis and preserve their catalytic activity in amide bond formation reactions. The catalysts are compatible with a range of functional groups and heterocycles useful for medicinal, agrochemical, and material chemists. The robustness of the Lewis acid-POM complexes is further supported by the catalyst reuse without loss of activity. This prolific combination of Zr(IV)/Hf(IV) and POMs inaugurates a powerful class of catalysts for the amide bond formation, which overcomes key limitations of previously established Zr(IV)/Hf(IV) salts and boron-based catalysts.
- De Azambuja, Francisco,Parac-Vogt, Tatjana N.
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p. 10245 - 10252
(2019/11/03)
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- RUTHENIUM COMPLEXES AND THEIR USES AS CATALYSTS IN PROCESSES FOR FORMATION AND/OR HYDROGENATION OF ESTERS, AMIDES AND RELATED REACTIONS
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The present invention relates to novel Ruthenium complexes of formulae A1-A4 and their use, inter alia, for (1) dehydrogenative coupling of alcohols to esters; (2) hydrogenation of esters to alcohols (including hydrogenation of cyclic esters (lactones) or cyclic di-esters (di-lactones), or polyesters); (3) preparing amides from alcohols and amines—(including the preparation of polyamides (e.g., polypeptides) by reacting dialcohols and diamines and/or polymerization of amino alcohols and/or forming cyclic dipeptides from p-aminoalcohols; (4) hydrogenation of amides (including cyclic dipeptides, polypeptides and polyamides) to alcohols and amines; (5) hydrogenation of organic carbonates (including polycarbonates) to alcohols or hydrogenation of carbamates (including polycarbamates) or urea derivatives to alcohols and amines; (6) dehydrogenation of secondary alcohols to ketones; (7) amidation of esters (i.e., synthesis of amides from esters and amines); (8) acylation of alcohols using esters; (9) coupling of alcohols with water and a base to form carboxylic acids; and (10) preparation of amino acids or their salts by coupling of amino alcohols with water and a base. The present, invention further relates to the use of certain known Ruthenium complexes for the preparation of amino acids or their salts from amino alcohols.
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Paragraph 0279
(2017/10/18)
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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 0032
(2013/06/05)
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- HEAT-LABILE PRODRUGS
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Disclosed herein are heat-labile prodrugs, their preparation and uses.
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Page/Page column 21
(2008/12/08)
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- Cyclization-activated prodrugs. Synthesis, reactivity and toxicity of dipeptide esters of paracetamol
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Dipeptide esters of paracetamol were prepared in high yields. These compounds are quantitatively hydrolyzed to paracetamol and corresponding 2,5-diketopiperazines at pH 7.4 and 37°C. The reactivity is increased in sarcosine and proline peptides and decreased by bulky side chains at both the N- and C-terminal residues of the dipeptide carrier. Moreover, dipeptide esters of paracetamol did not affect the levels of hepatic glutathione. Thus, dipeptides seem promising candidates as carriers for cyclization-activated prodrugs.
- Santos, Cledir,Mateus, Maria Luisa,Dos Santos, Ana Paula,Moreira, Rui,De Oliveira, Eliandre,Gomes, Paula
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p. 1595 - 1598
(2007/10/03)
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- A novel one step approach to the synthesis of 3H-1,4-benzodiazepin-(1H,4H)-2,5-diones from 1,2,3-benzotriazin-4-(3H)-one
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1,2,3-Benzotriazin-4-(3H)-one(3) and its 6-chloro derivative (4) on thermal condensation with α-amino acids yielded 3H-1,4-benzodiazepin-(1H,4H)-2,5-diones(7-12) in moderate to good yield. The cyclocondensation is believed to proceed through the formation of an iminoketene intermediate (5).
- Gupta, Renu,Sirohi, Reenu,Shastri, Sudha,Kishore
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p. 363 - 366
(2007/10/03)
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- Piperizinones as modulators of chemokine receptor activity
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The present application describes modulators of CCR3 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.
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- Metal-catalyzed hydroxylaminolysis of unactivated amide and peptide bonds.
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Kinetics of the hydroxylaminolysis of acetamide, glycinamide, glycylglycine and triglycine have been studied in the range of temperatures 37-60 degrees C as a function of pH and hydroxylamine concentration. Rate constants for specific acid, general-acid and general-base catalyzed pathways have been determined for all substrates (for glycine derivatives rate constants for different protonation forms were obtained). Testing different metal ions as possible reaction catalysts revealed a significant catalytic effect of Zn(II) on the hydroxylaminolysis of glycine substrates, but not acetamide. On the basis of the kinetic results, a mechanism of Zn(II) catalysis is proposed, which involves the coordination of the metal ion to the alpha-amino group of the substrate and the base-assisted nucleophilic attack of hydroxylamine on the bound substrate. The product analysis by proton NMR shows that the primary reaction product in the catalytic reaction is glycine hydroxamic acid, which undergoes further Zn(II)-catalyzed hydrolysis to glycine. Thus the final result of the Zn(II)-catalyzed treatment of peptides by hydroxylamine is hydrolytic cleavage.
- Gomez-Reyes, Baldomero,Yatsimirsky, Anatoly K
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p. 866 - 872
(2007/10/03)
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- Absolute rate constants for the formation of nitrogen-centred radicals from chloramines/amides and their reactions with antioxidants
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Pulse radiolysis techniques have been employed to investigate the one-electron reduction of a variety of chloramines and chloramides. These include models for the side-chain of Lys (6-aminohexanoic acid chloramine and α-N-acetyl-Lys chloramine), Gly chloramine, β-alanine chloramine and two models of protein backbone amides, the chloramides of cyclo-(Gly)2 and cyclo-(Ala)2. The molar absorption coefficients and stabilities of these chloramines/amides have been determined. The one-electron reduction of these chloramine/amide species by hydrated electrons occurs with second-order rate constants of the order of 109-1010 M-1 s-1, and results in cleavage of the N-Cl bonds to yield nitrogen-centred radicals and chloride ions (as measured by high performance ion chromatography). The reactivities of the nitrogen-centred radicals have been investigated with the readily oxidisable quenchers, hydroquinone and Trolox. These quenchers were used as models of the in vivo antioxidants, ubiquinol-10 and α-tocopherol, and react with second-order rate constants between 2 × 107 and 1 × 108 M-1 s-1. No evidence was obtained in these pulse radiolysis experiments for a rapid rearrangement of the oxidising nitrogen-centred radicals to reducing carbon-centred radicals, though such reactions have been indicated in previous EPR studies.
- Pattison, David I.,Davies, Michael J.,Asmus, Klaus-Dieter
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p. 1461 - 1467
(2007/10/03)
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- Five- and six-membered ring opening of pyroglutamic diketopiperazine
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A variety of ring-opening reactions of pyroglutamic diketopiperazine at both the five-membered and six-membered rings is described. Mild, basic conditions facilitate nucleophilic attack by amines at the diketopiperazine carbonyls giving pyroglutamides in excellent yield. Reaction with nucleophiles under acidic conditions give bis-glutamate derivatives of 2,5-diketopiperazine (DKP). These reactions provide simple, two-step sequences to pyroglutamides and symmetrical diketopiperazines from commercial pyroglutamic acid with control of product dictated by reaction conditions, catalyst, and nucleophile.
- Parrish, Dennis A.,Mathias, Lon J.
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p. 1820 - 1826
(2007/10/03)
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- Pharmaceutical diketopiperazine compounds
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A diketopiperazine of formula (I): STR1 wherein each of R7 and R8 which may be the same or different; is hydrogen or a nitro group; Y is STR2 --O-- or --S--, wherein each of R9 and R10 which may be the same or different, is hydrogen or a nitro group; n is 0, 1 or 2; m is an integer of 1 to 6; each R6, which may be the same or different, is a C1 -C6 alkyl group; and X is selected from (i) a phenyl group of the following formula STR3 and the salts and esters thereof; have activity as inhibitors of plasminogen activator inhibitor.
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- NORRISH TYPE II PHOTO-DEACYLATION OF SEMICYCLIC IMIDES
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The photochemical deacylation of 1,4-diacyl-2,5-piperazinediones was found to proceed through the type II ketene eliminating process.
- Sera, Akira,Okada, Manabu,Ohhata, Akira,Yamada, Hiroaki,Itoh, Kuniaki,Kubo, Yasuo
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p. 1039 - 1046
(2007/10/02)
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- Synthesis of tert-Leucine and Related Amino Acids
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The 2,5-dialkoxypyrazines 3a and b were prepared in three steps from methyl glycinate hydrochloride (1) in an overall yield of 18 and 63 percent.Upon the addition of lithium organyls to 3b and subsequent acid hydrolysis the ethyl glycinates rac-7 were obtained.Key Words: tert-Leucine / Amino acids / Glycine cation equivalents / Bislactim ether method
- Groth, Ulrich,Huhn, Thomas,Porsch, Bettina,Schmeck, Carsten,Schoellkopf, Ulrich
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p. 715 - 720
(2007/10/02)
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- SYNTHESIS OF DIPEPTIDE ESTERS OF METRONIDAZOLE AND EVALUATION OF THEIR HYDROLYTIC STABILITY
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Amino acid and dipeptide esters of metronidazole were synthesized and evaluated on their hydrolytic stability in various buffers and culture media.The hydrolytic susceptibility of the different esters was minimal in the pH range 3-5.In the alkaline region, pH 6.5-8, the half-lifes were of the order of 1-6.6 hrs.At alkaline pH the dipeptide esters were more susceptible towards hydrolysis.At pH 8.8 the observed half-life for the gly-gly and the gly-phe esters was 0.2 h, whereas for the gly and the phe ester it was 1.1 h, respectively 2.7 h.It was demonstrated that the increased rate of hydrolysis for the dipeptide esters was due to an intramolecular aminolysis with the formation of a diketopiperazine accompanied by the release of free metronidazole.
- Permentier, Dirk,Vansteenkiste, Stefan,Schacht, Etienne,Vermeersch, Hans,Remon, Jean Paul
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p. 701 - 708
(2007/10/02)
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- An Optically Active Nucleophile That Catches Its Substrate By Two Points
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Two diastereomeric cyclic dipeptides are obtained by coupling L or D-His with L-(crowned DOPA).The kinetic data on the reaction of p-nitrophenyl esters of protonated amino-acids and peptides with these His derivatives are reported.
- Janus, Stephan,Sonveaux, Etienne
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p. 3757 - 3760
(2007/10/02)
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- The Use of Crown Ethers in Peptide Chemistry. Part 2. Syntheses of Dipeptide Complexes with Cyclic Polyether 18-Crown-6 and their Derivatisation with DMSO
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As part of a study the aim of which is to use crown compounds as non-covalent protecting groups in peptide synthesis, we have explored the reactivity of 18-crown-6-ether-dipeptide complexes with dicyclohexylcarbodi-imide (DCC) in dimethyl sulphoxide (DMSO).At a reactant concentration of ca. 0.02 mol dm-3 the DCC did not activate the dipeptide, and the N-acylurea derivative slowly formed.At concentrations of ca. 0.2 mol dm-3 the complexes proved to be unstable and reacted with the solvent to form a DMSO-peptide adduct.The reaction mechanism leading to the latter was elucidated and shown to involve an initial acid-catalysed addition of DMSO to DCC.The presence in solution of nucleophiles gave the peptide ester thus indicating DCC-mediated activation of the peptide carboxylic acid group.The results from this study were used to design the conditions necessary for an effective non-covalent protection of the amino group during peptide synthesis.
- Hyde, Carolyn B.,Welham, Kevin J.,Mascagni, Paolo
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p. 2011 - 2016
(2007/10/02)
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- A Mechanism for bitter Taste Sensibility in Peptides
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To estimate the steric distance between the bitter taste determinant sites in peptides, some cyclic dipeptides, amino acid anilides, amino acid cyclohexylamides, and benzoyl amino acids were synthesized and their tastes were evaluated.The diketopiperazine ring of cyclic dipeptides acted as a bitter taste determinant site due to its hydrophobicity.The steric distance between 2 sites was estimated as 4.1 Angstroem from the molecule models of cyclic dipeptides composed of typical amino acids in the bitter peptides.Due to the hypothesis of two bitter taste determinant sites, which bind with the bitter taste receptor via a "binding unit" and a "stimulating unit," a mechanism for the bitterness in peptides was postulated.
- Ishibashi, Norio,Kouge, Katsushige,Shinoda,Ichizo,Kanehisa, Hidenori,Okai, Hideo
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p. 819 - 828
(2007/10/02)
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- TELOMERIZATION OF AMINO ACIDS WITH BUTADIENE, CATALYZED BY PALLADIUM COMPLEXES
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The telomerization of α, β, γ, and ε-amino acids having various structures with butadiene under the influence of the three-component palladium catalyst Pd(acac)2-PPh3-AlEt3 was investigated in DMSO-toluene solution.The α and ε-aliphatic and also the α, β, and γ-aromatic amino acids react with butadiene, giving the products from octadienylation at the amino group exclusively.Under the conditions of telomerization aliphatic β-amino acids are cleaved with the formation of unsaturated tertiary amines. in the case of aliphatic γ-amino acids it is possible to obtain telomers alkylated at the carbonyl group.
- Dzhemilev, U. M.,Fakhretdinov, R. N.,Telin, A. G.
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p. 1447 - 1456
(2007/10/02)
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- PHOTOADDITION REACTION OF 1,4-DIBROMO-2,5-PIPERAZINEDIONE WITH CYCLOHEXENE.
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The photo-induced addition reaction of 1,4-dibromo-2,5-piperazinedione (1) with cyclohexene in acetonitrile gave 1:1-adducts left bracket 1-(2-bromocyclohexyl)-2,5-piperazinediones right bracket and 1:2-adducts left bracket 1,4-bis(2-bromocyclohexyl)-2,5-piperazinediones right bracket besides 3-bromocyclohexene, 1,2-dibromocyclohexane, and a solvent-incorporated product, trans-2-acetylamino-2-bromocyclohexane. Stereochemistry of the adducts was elucidated and mechanism of the addition reaction was discussed.
- Itoh
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p. 1705 - 1709
(2007/10/02)
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- Peptide Decomposition in the Neutral pH Region via the Formation of Diketopiperazines
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In the neutral pH region, the decomposition of the tripeptides Leu-Gly-Gly and Gly-Leu-Gly at 130 deg C and the hexapeptide Phe-Gly-Leu-Gly-Val-Gly at 100 deg C has been found to involve the formation of diketopiperazines from the N-terminal position of the peptides.
- Steinberg, Spencer M.,Bada, Jeffrey L.
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p. 2295 - 2298
(2007/10/02)
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