Synthesis Of Dipeptides Research Articles

Sulfotyrosine dipeptide: Synthesis and evaluation as HIV-entry inhibitor

Human immunodeficiency virus type 1 (HIV-1) is responsible for the worldwide AIDS pandemic. Due to the lack of prophylactic HIV-1 vaccine, drug treatment of the infected patients becomes essential to reduce the viral load and to slow down progression of the disease. Because of drug resistance, finding new antiviral agents is necessary for AIDS drug therapies. The interaction of gp120 and co-receptor (CCR5/CXCR4) mediates the entry of HIV-1 into host cells, which has been increasingly exploited in recent years as the target for new antiviral agents. A conserved co-receptor binding site on gp120 that recognizes sulfotyrosine (sTyr) residues represents a structural target to design novel HIV entry inhibitors. In this work, we developed an efficient synthesis of sulfotyrosine dipeptide and evaluated it as an HIV-1 entry inhibitor.

Synthesis of a Tyr-Tyr Peptide Library and Fluorescence of the Stilbenyl Derivatives

An expeditious ultrasound–assisted synthesis of a tyrosine–tyrosine peptide library is presented. Dipeptide synthesis and functionalization, via Suzuki-Miyaura or Sonogashira cross-coupling reactions, was carried out and led to sixteen extended conjugation derivatives in moderate to good yields. Both o-hydroxy- and o-methoxy-trans-stilbenyl-Tyr-Tyr peptides emit blue fluorescence when irradiated with ultraviolet light. The fluorescence quantum yield of solutions of these peptides in methanol, acetonitrile or THF was 0.20 ± 0.05. Quantum chemical calculations at the Time-Dependent Density Functional Theory (TDDFT) level suggests that, for both peptides, emission originates from the stilbene core.

Brønsted Acid Catalyzed Peptide Synthesis through Azlactone Rings

Brønsted acid catalyzed azlactone ring opening by amino acids leading to the synthesis of dipeptides is presented. Eleven compounds were synthesized in good to excellent isolated yields. Catalyst loading revealed that 5.0 mol % of (+/-)-CSA as an organocatalyst, under room temperature for 24 h, was suitable to promote this transformation. Keywords: Azlactones, peptides, amino acids, organocatalysis, Brønted acid, (+/-)-camphorsulfonic acid.

Effective production of Pro–Gly by mutagenesis of l-amino acid ligase

l-Amino acid ligase (Lal) catalyzes dipeptide synthesis from unprotected l-amino acids by hydrolysis ATP to ADP. Each Lal displays unique substrate specificity, and many different dipeptides can be synthesized by selecting suitable Lal. We have already successfully synthesized Met-Gly selectively by replacing the Pro85 residues of Lal from Bacillus licheniformis (BL00235). From these results, we deduced that the amino acid residue at position 85 had a key role in enzyme activity, and applied these findings to other Lals. When Pro and Gly were used as substrates, TabS from Pseudomonas syringae, synthesized the salt taste enhancing dipeptide Pro-Gly and other three dipeptides (Gly-Pro, Pro-Pro, and Gly-Gly) was hardly synthesized from its substrate specificity. However, the amount of Pro-Gly was low. Therefore, to alter the substrate specificity and increase the amount of Pro-Gly, we selected amino acid residues that might affect the enzyme activity, Ser85 corresponding to Pro85 of BL00235, and His294 on the results from previous studies and the predicted structure of TabS. These residues were replaced with 20 proteogenic amino acids, and Pro-Gly synthesizing reactions were conducted. The S85T and the H294D mutants synthesized more Pro-Gly than wild-type. Furthermore, the S85T/H294D double mutant synthesized considerably more Pro-Gly than the single mutant did. These results showed that the amino acid position 85 of TabS affect the enzyme activity similarly to BL00235. In addition, replacing the amino acid residue positioning around the N-terminal substrate and constructing the double mutant led to increase the amount of Pro-Gly.

Effect of spacer modification on enzymatic synthetic and hydrolytic activities of immobilized trypsin

A thorough comparison of spacer-mediated covalent and non-covalent immobilization of trypsin on micro-magnetic particles was accomplished in the present study. Trypsin was coupled via diaminoalkanes, aminoalkanoic acids, bovine serum albumin (BSA), and biotin-derivate spacers onto magnetic particles. A comparison of resulting synthetic and hydrolytic activities after immobilization was performed. Whereas hydrolytic trypsin activity was measured employing N-α-benzoyl-dl-arginine 4-nitroanilide (BAPNA) assay, synthetic trypsin activity was measured employing a dipeptide synthesis assay. Within spacer-mediated trypsin immobilization, diaminoalkanes, aminoalkanoic acids and biotin spacers showed up to 40% increased synthetic specific activity of trypsin compared to the spacer-free method. Within the hydrolytic reaction type, coupling of trypsin via diaminoalkanes and biotin spacers resulted in a specific activity increase of up to 30%. BSA-bound trypsin displayed only minor increasing effects on both activities of trypsin. Furthermore, protein loading-dependent specific synthetic and hydrolytic activities were evaluated for 8-aminooctanoic acid, 12-aminododecanoic acid and 1,12-diamonododecane as spacers and compared to the direct covalent binding method. The protein binding capacity of spacer-modified particles was lower compared to the direct binding method. Synthetic activity of 8-aminooctanoic acid-bound trypsin was higher than in the case of the spacer-free method over a broad protein loading range with an up to 10-fold increase. The hydrolytic activity was increased by 64% using 8-aminooctanoic acid as spacer within a lower protein loading range. Spacer-bound trypsin showed a slightly lowered reusability over ten sequential cycles compared to spacer-free covalent binding method.

ChemInform Abstract: Coupling‐Reagent‐Free Synthesis of Dipeptides and Tripeptides Using Amino Acid Ionic Liquids.

AbstractThe procedure is based on the reaction of HCl salts of amino acid methyl esters with 5.4 equiv.

Synthesis of Dipeptide and Carbohydrate Ivermectin B1 Derivatives

Synthesis of Dipeptide and Carbohydrate Ivermectin B1 Derivatives

Solid-Phase Peptide Synthesis of Dipeptide (Histidine-β-Alanine) as a Chelating Agent by Using Trityl Chloride Resin, for Removal of Al3+, Cu2+, Hg2+and Pb2+: Experimental and Theoretical Study

Solid-phase peptide synthesis of dipeptide (histidine-β-alanine) as a chelating agent examined by common N-9-fluorenylmethyloxycarbonyl-N-trityl-L-histidine and tert-butyloxycarbonyl-β-alanine-OH amino acid derivatives. Trityl chloride resin was used as a carrier resin. The molecular structure of the dipeptide was definite by using different methods such as ultraviolet visible (UV-Vis), Fourier transform infrared (FTIR), proton (1H) nuclear magnetic ressonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) and the chelating property of synthesized dipeptide was investigated for removing of metal ions Al3+, Cu2+, Hg2+ and Pb2+in vitro. In addition, the pharmacological and biological activities of dipeptide were examined by prediction of activity spectra for substances (PASS) program.

N,O-Bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents for dipeptide synthesis

Abstract A method using N,O -bis(trimethylsilyl)acetamide/ N -hydroxysuccinimide ester (BSA/NHS) as coupling agents for dipeptide synthesis is descried. The coupling reaction between N -hydroxysuccinimide (NHS) esters and amines could be performed under mild conditions with N,O -bis(trimethylsilyl)acetamide (BSA) as coupling reagent and no additional acid/base is required. All byproducts and excessive reactants are water soluble or hydrolysable and easy to eliminate through water-washing at the purification stage. Moreover, all the reactants are inexpensive and widely used in conventional drug production.

Corynebacterium glutamicum ggtB encodes a functional γ-glutamyl transpeptidase with γ-glutamyl dipeptide synthetic and hydrolytic activity

In this work the role of γ-glutamyl transpeptidase in the metabolism of γ-glutamyl dipeptides produced by Corynebacterium glutamicum ATCC 13032 was studied. The enzyme is encoded by the gene ggtB (cg1090) and synthesized as a 657 amino acids long preprotein. Gamma-glutamyl transpeptidase activity was found to be associated with intact cells of C. glutamicum and was abolished upon deletion of ggtB. Bioinformatic analysis indicated that the enzyme is a lipoprotein and is attached to the outer side of the cytoplasmic membrane. Biochemical parameters of recombinant GgtB were determined using the chromogenic substrate γ-glutamyl-p-nitroanilide. Highest activity of the enzyme was measured in sodium bicarbonate buffer at pH 9.6 and 45°C. The KM value was 123μM. GgtB catalyzed the concentration-dependent synthesis and hydrolysis of γ-glutamyl dipeptides and showed strong glutaminase activity. The intracellular concentrations of five γ-glutamyl dipeptides (γ-Glu-Glu, γ-Glu-Gln, γ-Glu-Val, γ-Glu-Leu, γ-Glu-Met) were determined by HPLC-MS and ranged from 0.15 to 0.4mg/g CDW after exponential growth in minimal media. Although deletion and overexpression of ggtB had significant effects on intracellular dipeptide concentrations, it was neither essential for biosynthesis nor catabolism of these dipeptides in vivo.

Practical Peptide Synthesis Mediated by a Recyclable Hypervalent Iodine Reagent and Tris(4-methoxyphenyl)phosphine.

6-(3,5-Bis(trifluoromethyl)phenyl)-1H,4H-2aλ(3)-ioda-2,3-dioxacyclopenta[hi]indene-1,4-dione (p-BTFP-iodosodilactone, 1a) was synthesized and demonstrated to be an efficient hypervalent iodine(III) reagent for the synthesis of dipeptides from various standard amino acids, including sterically hindered amino acids, in good to high yields within 30 min in the presence of tris(4-methoxyphenyl)phosphine. In addition, the combined system of 1a/(4-MeOC6H4)3P was used to synthesize the pentapeptide leu-enkephalin in protected form. It is worth noting that 1a can be regenerated readily after reaction.

Synthesis of Some Novel Class of Peptides from α‐Amino Nitrones and Their Potential Biological Activities

α‐amino nitrones are found to have a great significance in the synthesis of peptides. Simple reaction methodology, high yield, and atom efficiency in these reactions have made this protocol highly attractive. The synthetic route may be extended to the synthesis of dipeptides in enantiomerically pure form. Potential biological activity of the newly synthesized peptides is the major application in this new methodology.

Coupling-Reagent-Free Synthesis of Dipeptides and Tripeptides Using Amino Acid Ionic Liquids.

A general method for the synthesis of dipeptides has been developed, which does not require any coupling reagents. This method is based on the reaction of readily available HCl salts of amino acid methyl esters with tetrabutylphosphonium amino acid ionic liquids. The isolation procedure of stepwise treatment with AcOH is easy to carry out. The method was extended to the synthesis of tripeptide, tyrosyl-glycyl-glycine, present in IMREG-1, also.

Solution-Phase Synthesis of Dipeptides: A Capstone Project That Employs Key Techniques in an Organic Laboratory Course

A contemporary approach to the synthesis and purification of several UV-active dipeptides has been developed for the second-year organic laboratory. This experiment exposes students to the important technique of solution-phase peptide synthesis and allows an instructor to highlight the parallel between what they are accomplishing in the laboratory to the advancements being made in the pharmaceutical industry. By illustrating the importance of protecting group strategy and stereochemistry preservation, while also reinforcing the various separatory and purification techniques learned throughout the typical laboratory course, this experiment serves as an excellent candidate for a capstone project that assesses students’ mastery of important techniques learned in an introductory organic laboratory course.

Synthesis and antiproliferative activity of glutamic acid-based dipeptides

A small and focused library of 22 dipeptides derived from N,N-dibenzylglutamic acid α- and γ-benzyl esters was prepared in a straightforward manner. The evaluation of the antiproliferative activity in the human solid tumor cell lines HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast), and WiDr (colon) provided γ-glutamyl methionine (GI50 = 6.0-41 μM) and α-glutamyl proline (GI50 = 7.5-18 μM) as lead compounds. In particular, glutamyl serine and glutamyl proline dipeptides were more active in the resistant cancer cell line WiDr than the conventional anticancer drugs cisplatin and etoposide. Glutamyl tryptophan dipeptides did not affect cell growth of HBL-100, while in T-47D cells, proliferation was inhibited. This result might be attributed to the inhibition of the ATB(0,+) transporter.

Catalytic chemical amide synthesis at room temperature: one more step toward peptide synthesis.

An efficient method has been developed for direct amide bond synthesis between carboxylic acids and amines via (2-(thiophen-2-ylmethyl)phenyl)boronic acid as a highly active bench-stable catalyst. This catalyst was found to be very effective at room temperature for a large range of substrates with slightly higher temperatures required for challenging ones. This methodology can be applied to aliphatic, α-hydroxyl, aromatic, and heteroaromatic acids as well as primary, secondary, heterocyclic, and even functionalized amines. Notably, N-Boc-protected amino acids were successfully coupled in good yields with very little racemization. An example of catalytic dipeptide synthesis is reported.

Synthesis of dipeptide mimics based on amino phosphinate backbones and cyclic derivatives

Dialkyl phosphinates are valuable peptide mimics fo r metallopeptidase targets. Despite their large pharmaceutical potential, the synthesis of many pho sphinates remains challenging. An additional drawback for many applications is the high polarity of the phosphinate group. Herein we describe the synthesis of stereoisomerically pure GPI ( 1), a phosphinate with high binding affinity for the cancer specific zinc peptidase PSMA (prostate speci fic membrane antigen). In addition, analogous cyclic phosphinate esters 13 , 16 and 23 are reported that might be useful as less polar li gands for metallo peptidase binding. The key step to these ne w 1,2-oxaphosphorinan-2-ones is an intramolecular cyclization of an intermediate H-phosphinate. The cyclizations work with modest diastereoselectivities of ~2:1 in favor of the trans arrangement of substituents at 2- and 4-position of the 1,2-oxaphosphorinan-2-one scaffolds.

A robust synthesis of N-glycolyl muramyl dipeptide via azidonitration/reduction.

A novel synthetic route leading to N-glycolyl muramyl dipeptide (MDP), a bacterial glycopeptide of particular interest in studies of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), is described. The synthetic strategy hinges on the alkylation of benzylidene-protected glucal with 2-bromopropionic acid and thus circumvents a challenging and non-reproducible SN2 step at the C-3 position of glucosamine derivatives. The subsequent sequence includes an azidonitration and an unusual azide reduction/acylation step via an aza ylide/oxaphospholidine intermediate. This approach generates a protected N-glycolyl MDP that can be either subjected to a one-step global deprotection or differentially deprotected to obtain further derivatives.

A green route for the synthesis of a bitter-taste dipeptide combining biocatalysis, heterogeneous metal catalysis and magnetic nanoparticles

The combo protease-metal catalyst-magnetic nanoparticles was used to establish a green alternative synthetic route to produce the bitter taste dipeptide Ala-Phe.

Synthesis, Absorption, and Fluorescence Studies of Coumaryl-Labelled Amino Acids and Dipeptides Linked Via Triazole Ring

Fluorophores based on 4-triazolyl, 7-hydroxy-4-triazolylmethyl, 4-O-triazolylmethyl, and 7-O-triazolylmethyl coumaryl-tagged amino acids and dipeptides were synthesized by copper-catalyzed [3 + 2] cycloaddition reaction between azido- or alkynyl-functionalized coumarins with alkynyl- or azido-functionalized amino acid and dipeptides in good-to-excellent yields. Steady-state absorption and the fluorescence properties of the synthesized conjugates were studied. The chemical applicability of these amino acid and peptide-based fluorophores was successfully demonstrated by their linear elongation by further tagging them with appropriate C- or N-terminus amino acid.