Coupling Reagent For Peptide Synthesis Research Articles

Ynamide-Mediated Peptide Bond Formation: Mechanistic Study and Synthetic Applications.

Ynamides, a class of novel coupling reagents for peptide synthesis, facilitated peptide bond formation in a one-pot, two-step manner with α-acyloxyenamide active esters of amino acids as stable intermediates. Ynamide-mediated peptide synthesis proceeded by a reaction mechanism that is completely different from that of conventional coupling reagents and exhibited superiority in addressing the issue of racemization/epimerization during peptide bond formation. Herein, we present a systematic mechanistic analysis, including kinetics and Brønsted-type structure-reactivity studies and density functional theory calculations, providing unprecedented mechanistic insight into ynamide-mediated peptide bond formation. Based on these mechanistic studies, significant improvements were made, and the applicability of ynamide-mediated peptide bond formation was successfully expanded to peptide fragment condensation, head-to-tail cyclization and solid-phase peptide synthesis.

Ynamide‐Mediated Peptide Bond Formation: Mechanistic Study and Synthetic Applications

AbstractYnamides, a class of novel coupling reagents for peptide synthesis, facilitated peptide bond formation in a one‐pot, two‐step manner with α‐acyloxyenamide active esters of amino acids as stable intermediates. Ynamide‐mediated peptide synthesis proceeded by a reaction mechanism that is completely different from that of conventional coupling reagents and exhibited superiority in addressing the issue of racemization/epimerization during peptide bond formation. Herein, we present a systematic mechanistic analysis, including kinetics and Brønsted‐type structure–reactivity studies and density functional theory calculations, providing unprecedented mechanistic insight into ynamide‐mediated peptide bond formation. Based on these mechanistic studies, significant improvements were made, and the applicability of ynamide‐mediated peptide bond formation was successfully expanded to peptide fragment condensation, head‐to‐tail cyclization and solid‐phase peptide synthesis.

1H-Fluoren-9-ylmethyl Chloroformate as a Coupling Reagent for Peptide Synthesis

1H-Fluoren-9-ylmethyl Chloroformate as a Coupling Reagent for Peptide Synthesis

Design and Synthesis of a Thiazolium-Based Coupling Reagent for Peptide Synthesis

Design and Synthesis of a Thiazolium-Based Coupling Reagent for Peptide Synthesis

Propargyl Pentafluorophenyl Carbonate as a Coupling Reagent for Peptide Synthesis

Key words propargyl pentafluorophenyl carbonate - peptide synthesis - coupling reagent

Bis(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl) Ether as Coupling Reagent for Peptide Synthesis

Bis(4,6-dimethoxy-1,3,5-triazin-2-yl) ether (4) was prepared by treatment of 2-hydroxy-4,6-dimethoxy-1,3,5-triazine with 2-chloro-4,6-dimethoxy-1,3,5-triazine in 61% yield. Ether 4, isoelectronic with pyrocarbonates, was found capable to activate carboxylic acids in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to yield, under mild reaction conditions, superactive triazine esters. Versatility of this new coupling reagent was confirmed by condensation of lipophilic and sterically hindered carboxylic acids with amines in 71-98% yield, and by synthesis of peptides, including those containing Aib-Aib sequence, in solution with high yield and high enantiomeric purity.

Diisopropylcarbodiimide

N,N′-Diisopropylcarbodiimide (DIC) is a liquid carbodiimide used in peptide synthesis and contains the functional group RN=C=NR. Carbodiimides hydrolyze to form ureas, which makes them uncommon in nature. Between the different sources of carbodiimide coupling reagents in peptide synthesis, the use of DIC as a liquid carbodiimide is more convenient. By using DIC one can avoid the tedious removal of dicyclohexylurea (DCU) formed during the use of dicyclohexylcarbodiimide (DCC),[ 1 ] as diisopropylurea (DIU) is comparatively easy to remove at the time of purification, which is formed after the generation of peptide bond. Besides being a less expensive and commercially available reagent, DIC is a good coupling agent and widely used in solid-phase peptide synthesis. As a liquid, it is easier to handle than the commonly used DCC.

A Synthetic S6 Segment Derived from KvAP Channel Self-assembles, Permeabilizes Lipid Vesicles, and Exhibits Ion Channel Activity in Bilayer Lipid Membrane

KvAP is a voltage-gated tetrameric K(+) channel with six transmembrane (S1-S6) segments in each monomer from the archaeon Aeropyrum pernix. The objective of the present investigation was to understand the plausible role of the S6 segment, which has been proposed to form the inner lining of the pore, in the membrane assembly and functional properties of KvAP channel. For this purpose, a 22-residue peptide, corresponding to the S6 transmembrane segment of KvAP (amino acids 218-239), and a scrambled peptide (S6-SCR) with rearrangement of only hydrophobic amino acids but without changing its composition were synthesized and characterized structurally and functionally. Although both peptides bound to the negatively charged phosphatidylcholine/phosphatidylglycerol model membrane with comparable affinity, significant differences were observed between these peptides in their localization, self-assembly, and aggregation properties onto this membrane. S6-SCR also exhibited reduced helical structures in SDS micelles and phosphatidylcholine/phosphatidylglycerol lipid vesicles as compared with the S6 peptide. Furthermore, the S6 peptide showed significant membrane-permeabilizing capability as evidenced by the release of calcein from the calcein-entrapped lipid vesicles, whereas S6-SCR showed much weaker efficacy. Interestingly, although the S6 peptide showed ion channel activity in the bilayer lipid membrane, despite having the same amino acid composition, S6-SCR was significantly inactive. The results demonstrated sequence-specific structural and functional properties of the S6 wild type peptide. The selected S6 segment is probably an important structural element that could play an important role in the membrane interaction, membrane assembly, and functional property of the KvAP channel.

ChemInform Abstract: HOBt and HOAt-Derived Immonium Salts: New and Highly Efficient Coupling Reagents for Peptide Synthesis.

Abstract Novel HOBt- and HOAt-derived immonium type coupling reagents BDMP, BPMP and AOMP were shown to be very efficient for peptide synthesis with high reactivity, low racemization and good yields. X-Ray analysis indicates BOMI exists as the N-substituted form rather than as the O-substituted form assigned previously. A mechanism for amide bond formation mediated by these reagents was proposed and studied.

Targeting of PED/PEA-15 Molecular Interaction with Phospholipase D1 Enhances Insulin Sensitivity in Skeletal Muscle Cells

Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) is overexpressed in several tissues of individuals affected by type 2 diabetes. In intact cells and in transgenic animal models, PED/PEA-15 overexpression impairs insulin regulation of glucose transport, and this is mediated by its interaction with the C-terminal D4 domain of phospholipase D1 (PLD1) and the consequent increase of protein kinase C-alpha activity. Here we show that interfering with the interaction of PED/PEA-15 with PLD1 in L6 skeletal muscle cells overexpressing PED/PEA-15 (L6(PED/PEA-15)) restores insulin sensitivity. Surface plasmon resonance and ELISA-like assays show that PED/PEA-15 binds in vitro the D4 domain with high affinity (K(D) = 0.37 +/- 0.13 mum), and a PED/PEA-15 peptide, spanning residues 1-24, PED-(1-24), is able to compete with the PED/PEA-15-D4 recognition. When loaded into L6(PED/PEA-15) cells and in myocytes derived from PED/PEA-15-overexpressing transgenic mice, PED-(1-24) abrogates the PED/PEA-15-PLD1 interaction and reduces protein kinase C-alpha activity to levels similar to controls. Importantly, the peptide restores insulin-stimulated glucose uptake by approximately 70%. Similar results are obtained by expression of D4 in L6(PED/PEA-15). All these findings suggest that disruption of the PED/PEA-15-PLD1 molecular interaction enhances insulin sensitivity in skeletal muscle cells and indicate that PED/PEA-15 as an important target for type 2 diabetes.

ChemInform Abstract: Sulfonates of N‐Triazinylammonium Salts as Highly Efficient, Inexpensive and Environmentally Friendly Coupling Reagents for Peptide Synthesis

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Morpholine-Based Immonium and Halogenoamidinium Salts as Coupling Reagents in Peptide Synthesis1

Here we describe a new family of N-form immonium-type coupling reagents that differ in their carbocation skeleton structure. The N-methylpiperazine derivative failed to form immonium salts, while the thiomorpholine derivative did not give better results than the coupling reagents currently used. The presence of the morpholine had a marked influence on the solubility and stability as well as the reactivity of the reagent. Finally, the fluoroamidinium salt performed extremely well in the presence of only 1 equiv of base, thereby confirming the effect of the proton acceptor in the reaction.

Structural basis for superiority of quaternaryN-triazynylammonium tetrafluoroborates as new coupling reagents in peptide synthesis

Structural basis for superiority of quaternary<i>N</i>-triazynylammonium tetrafluoroborates as new coupling reagents in peptide synthesis

Organophosphorus and Nitro‐Substituted Sulfonate Esters of 1‐Hydroxy‐7‐azabenzotriazole as Highly Efficient Fast‐Acting Peptide Coupling Reagents.

Organophosphorus esters 9, 10, 14, and 15 prepared via reaction of diethyl- and diphenylphosphoryl chloride, di(o-tolyl)phosphinyl chloride, and 2,8-dimethylphenoxaphosphinyl chloride with HOAt are excellent coupling reagents for peptide synthesis which are generally superior to their uronium/guanidinium analogues and HOBt- or HODhbt-derived phosphate ester counterparts in minimizing loss of configuration during segment coupling. The phosphinyl analogues are more shelf-stable than the phosphoryl systems. The new reagents have been tested in segment couplings leading to two tripeptides (20, 21) and a hexapeptide 22. Outstanding utility is also shown for the solid-phase assembly of the ACP decapeptide. Similar results were obtained with the 2- and 4-nitro- and 2,4-dinitrophenylsulfonyl esters derived from HOAt.

Organophosphorus and nitro-substituted sulfonate esters of 1-hydroxy-7-azabenzotriazole as highly efficient fast-acting peptide coupling reagents.

Organophosphorus esters 9, 10, 14, and 15 prepared via reaction of diethyl- and diphenylphosphoryl chloride, di(o-tolyl)phosphinyl chloride, and 2,8-dimethylphenoxaphosphinyl chloride with HOAt are excellent coupling reagents for peptide synthesis which are generally superior to their uronium/guanidinium analogues and HOBt- or HODhbt-derived phosphate ester counterparts in minimizing loss of configuration during segment coupling. The phosphinyl analogues are more shelf-stable than the phosphoryl systems. The new reagents have been tested in segment couplings leading to two tripeptides (20, 21) and a hexapeptide 22. Outstanding utility is also shown for the solid-phase assembly of the ACP decapeptide. Similar results were obtained with the 2- and 4-nitro- and 2,4-dinitrophenylsulfonyl esters derived from HOAt.

Assessment of new 6-Cl-HOBt based coupling reagents for peptide synthesis. Part 1: Coupling efficiency study

The efficiency of a series of well-known coupling reagents (TBTU, HATU, and PyBOP) and of newin situ activating reagents (TCTU, HCTU, and DMTMM) was compared by synthesizing the 65–74 fragment of the Acyl Carrier Protein (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-NH2), containing ‘a difficult sequence’, as a test peptide, in a multiple peptide synthesizer. The longer sequence rMOG(35–55) was also synthesized. It was clear that the aminium salts are more efficient than the phosphonium salt (PyBOP) and that the new 6Cl-HOBt based reagents (HCTU and particularly TCTU) are very efficient, while DMTMM appeared to be not suitable for SPPS.

Assessment of new 6-Cl-HOBt based coupling reagents for peptide synthesis. Part 2: Racemization studies

Novel Cl-HOBt based coupling reagents have been evaluated for racemization extent in solid-phase peptide synthesis. The results show that all the coupling protocols based on the use of the novel reagents enable incorporation of the racemization prone residue serine with less than 2% racemization. Moreover, serine racemization obtained is less than 0.5% with protocols where a pre-activation step is avoided.

HOBt and HOAt-derived immonium salts: new and highly efficient coupling reagents for peptide synthesis

Novel HOBt- and HOAt-derived immonium type coupling reagents BDMP, BPMP and AOMP were shown to be very efficient for peptide synthesis with high reactivity, low racemization and good yields. X-Ray analysis indicates BOMI exists as the N-substituted form rather than as the O-substituted form assigned previously. A mechanism for amide bond formation mediated by these reagents was proposed and studied.

Understanding the structure/reactivity of aminium/uronium salts as coupling reagents in peptide synthesis

Coupling reagents based on onium (aminium/uronium) salts based on HOBt and HOAt are more frequently used in solid-phase peptide synthesis than the classical carbodiimide methods. The structure of the carbon skeleton has a determining role in the efficiency of the reagent for the activation step. Simple theoretical calculations using the AM1 semiempirical Hamiltonian as implemented in the MOPAC program provide a rational way to correlate the reactivity of different aminium/uronium salts with the structure of the carbon skeleton.

ChemInform Abstract: Total Synthesis of Dehydrodidemnin B. Use of Uronium and Phosphonium Salt Coupling Reagents in Peptide Synthesis in Solution.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.