Sequential native chemical ligation utilizing peptide thioacids derived from newly developed Fmoc-based synthetic method

The first facile Fmoc-based synthetic procedure for peptide thioacids was developed. Successful application of the resulting thioacids to sequential native chemical ligation (NCL) in the N to C direction was achieved. Conversion of the peptide thioacids to the corresponding thioesters with Ellman's reagent followed by NCL in the presence of tris(2-carboxyethyl)phosphine (TCEP) and thiophenol was accomplished in a one-pot manner.     

Subtiligase as a hydrothiolase for the synthesis of peptide thioacids

Subtiligase catalyzes the hydrolysis or the aminolysis of a peptide glycolate ester substrate via an acyl-enzyme thioester intermediate. We show that this intermediate can be intercepted by a hydrosulfide ion to generate a peptide thioacid as the hydrothiolysis product. Also shown is the use of the so-prepared peptide thioacids in mini thiol capture ligation.     

Synthesis of a thioester linker precursor for a general preparation of peptide C-terminal thioacids

A general procedure to prepare peptide thioacids by solid-phase peptide synthesis is presented. The method involves the synthesis of 4-[α-(S-acetyl)mercaptobenzyl]phenoxyacetic acid as general precursor. This reagent once attached to a solid support is derivatized with the Boc-amino acid of choice after deprotection of the thiol.     

Amino acid and peptide synthesis and functionalization by the reaction of thioacids with 2,4-dinitrobenzenesulfonamides

Readily prepared amino thioacids react at room temperature in DMF in the presence of cesium carbonate with 2,4-dinitrobenzenesulfonamides to give amides. When the sulfonamide is derived from an amino acid the method results in peptide bond formation, whereas the use of carbohydrate derived sulfonamides gives neoglycoconjugates.     

Thio-mediated synthesis of derivatized N-linked glycopeptides using isonitrile chemistry

The reaction of oligosaccharide isonitriles with peptide thioacids in the presence of bulky thiophenol as activator to provide N-linked glycopeptides at room temperature is described.     

Mixed-phase synthesis of glycopeptides using a N-peptidyl-2,4-dinitrobenzenesulfonamide-thioacid ligation strategy

A strategy for the solid phase peptide synthesis (SPPS) and coupling of N-peptidyl and N-glycopeptidyl 2,4-dinitrobenzenesulfonamides (dNBS) with C-terminal peptidyl thioacids has been developed. The resulting N-dDNBS peptides were coupled to generate longer peptides. Ligation reactions were complete within 15 to 20 min.     

Aziridine‐Mediated Ligation at Phenylalanine and Tryptophan Sites

An efficient approach towards peptide synthesis that allows easy access to variety of small peptides via one‐pot aziridine‐mediated ligation/desulfurization strategy has been described. The protocol afforded a library of phenylalanine‐ and tryptophan‐containing α‐peptides in good yields by regioselective ring‐opening of aziridine‐3‐aryl‐2‐carboxylates with peptide thioacids, followed by desulfurization.     

Copper(II) mediated facile and ultra fast peptide synthesis in methanol

A novel, ultrafast, mild and scalable amide bond formation strategy in methanol using simple thioacids and amines is described. The mechanism suggests that the coupling reactions are initially mediated by CuSO(4)·5H(2)O and subsequently catalyzed by in situ generated copper sulfide. The pure peptides were isolated in satisfactory yields in less than 5 minutes.     

Resin-bound sulfonyl azides: efficient loading and activation strategy for the preparation of the N-acyl sulfonamide linker

This paper describes an optimized protocol for the efficient loading of resin-bound aminoethane sulfonyl azides by either Boc- or Fmoc-protected amino thioacids. The resulting N-acyl sulfonamide is a convenient linker for use in Boc- or Fmoc-based solid-phase peptide synthesis. Activation of the N-acyl sulfonamide via a microwave-assisted alkylation procedure and subsequent treatment with functionalized nucleophiles yields C-terminally modified peptides that can be applied in chemoselective (bio)conjugation or ligation reactions.     

Aziridine-mediated ligation and site-specific modification of unprotected peptides

A synthesis of aziridine-containing peptides via the Cu(II)-promoted coupling of unprotected peptide thioacids and N-H aziridine-2-carbonyl peptides is reported. The unique reactivity of the resulting N-acylated aziridine-2-carbonyl peptides facilitates their subsequent regioselective and stereoselective nucleophilic ring-opening to give unprotected peptides that are specifically modified at the ligation site. The aziridine-mediated peptide ligation concept is exemplified using H(2)O as the nucleophile, producing a Xaa-Thr linkage (where Xaa can be an epimerizable and hindered amino acid). The overall process is compatible with a variety of unprotected amino acid functionality, most notably the N-terminal and Lys side chain amines.     

A Tripeptide Approach to the Solid-Phase Synthesis of Peptide Thioacids and N-Glycopeptides

A general and robust method for the incorporation of aspartates with a thioacid side chain into peptides has been developed. Pseudoproline tripeptides served as building blocks for the efficient fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis of thioacid-containing peptides. These peptides were readily converted to complex N-glycopeptides by using a fast and chemoselective one-pot deprotection/ligation procedure. Furthermore, a novel side reaction that can lead to site-selective peptide cleavage using thioacids (CUT) was discovered and studied in detail.     

T3P (propylphosphonic anhydride) mediated conversion of Nα-protected amino/peptide acids into thioacids

A general, mild and an efficient protocol, which makes use of T3P as an acid activator for the synthesis of N^α-protected amino/peptide thioacids from corresponding acids in the presence of finely ground Na₂S as hydrosulfide ion donor is described. The protocol employed significantly increases the overall efficiency as the yield, reaction duration and purity of even sterically hindered amino acids.     

Coupling reactions of hindered isonitriles and hindered alkyl thioacids: mechanistic studies

The coupling reaction between hindered thioacids and isonitriles is developed and described. The mechanism for the formation of the thiopyruvamide products is explored, and the method is applied to a selection of substrates.     

Preparation and reactions of N-thioformyl peptides from amino thioacids and isonitriles

The preparation of N-thioformyl peptides from amino thioacids and isonitriles at room temperature is described.     

Kinetics and Mechanism of the Oxidation of Some Thioacids by Hexamethylenetetramine-Bromine

Oxidation of thioacids by hexamethylenetetramine-bromine proceeds through an intermediate complex in the pre-equilibrium and its subsequent decomposition in the slow step.     

New Type of Molecular Propellers with Acyclic Blades Stabilised by Phosphorus Atropoisomerism

Here we report on a new type of chiral molecular propellers - trianhydrides of trithiophosphorous acid and organic thioacids.     

ADDITION of THIO COMPOUNDS to (R)-LIMONENE CATALYZED by AMBERLYST-15

The addition of thioacids and thiophenol to (R)-limonene catalyzed by Amberlyst-15 produced the corresponding 9-thioester- or 9-thioether-p-menthene chemo- and regioselectively.     

Thermodynamics of peptide dimer formation

The Replica Exchange Statistical Temperature Molecular Dynamics algorithm is used to study the equilibrium properties of a peptide monomer and dimer and the thermodynamics of peptide dimer formation. The simulation data are analyzed by the Statistical Temperature Weighted Histogram Analysis Method. Each 10-residue peptide is represented by a coarse-grained model with hydrophobic side chains and has an α-helix as its minimum energy configuration. It is shown that the configurational behavior of the dimer can be divided into four regions as the temperature increases: two folded peptides; one folded and one unfolded peptide; two unfolded peptides; and two spatially separated peptides. Two important phenomena are discussed: in the dimer, one peptide unfolds at a lower temperature than the isolated monomer and the other peptide unfolds at a higher temperature than the isolated monomer. In addition, in the temperature region where one peptide is folded and the other unfolded, the unfolded peptide adopts an extended structure that minimizes the overall surface area of the aggregate. It is suggested that combination of destabilization due to aggregation and the resulting extended configuration of the destabilized peptide could have implications for nucleating β-sheet structures and the ultimate formation of fibrils.     

N-to-C solid-phase peptide and peptide trifluoromethylketone synthesis using amino acid tert-butyl esters

Solid-phase peptide synthesis in the N-to-C direction, opposite to the classical C-to-N direction of peptide synthesis, provides the synthetically versatile C-terminal carboxyl group for further modification into C-terminally modified peptide mimetics. These are of general interest as potential bioactive agents, particularly as protease inhibitors. Elaboration of peptide mimetics on the solid-phase would facilitate synthesis of peptide mimetic combinatorial libraries. This report describes an effective strategy for solid-phase inverse peptide synthesis based on readily available amino acid tert-butyl esters. The potential of this approach for peptide mimetic synthesis is demonstrated by the solid-phase synthesis of two peptide trifluoromethylketones.     

Construction of diverse peptide structural architectures via chemoselective peptide ligation

Herein, we report the development of a facile synthetic strategy for constructing diverse peptide structural architectures via chemoselective peptide ligation. The key advancement involved is to utilize the benzofuran moiety as the peptide salicylaldehyde ester surrogate, and Dap–Ser/Lys–Ser dipeptide as the hydroxyl amino functionality, which could be successfully introduced at the side chain of peptides enabling peptide ligation. With this method, the side chain-to-side chain cyclic peptide, branched/bridged peptides, tailed cyclic peptides and multi-cyclic peptides have been designed and successfully synthesized with native peptidic linkages at the ligation sites. This strategy has provided an alternative strategic opportunity for synthetic peptide development. It also serves as an inspiration for the structural design of PPI inhibitors with new modalities.

Methods of introducing peptide salicylaldehyde esters and hydroxyl amine functionality into the peptide side chain have been developed. Diverse peptide structural motifs were constructed via ligation with native amide linkages at the ligation sites.