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Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click synthesis of an Fmoc-(trispropargyl)amino acid building block for solid phase peptide synthesis (SPPS) of oligo-(trialkyne)peptide constructs is reported. These can carry potentially indefinite numbers of inherent alkyne-triplets, which are click derivatized with GlcNAc-azide into the corresponding glycopeptides. [ABSTRACT FROM AUTHOR]

The development of an entirely solid-phase peptide synthesis (SPPS)-based synthesis of the quorum sensing signal gelatinase biosynthesis-activating pheromone (GBAP) from Enterococcus faecalis is reported. The method was used to prepare three libraries of analogues to investigate the structure-activity relationships (SARs) of the GBAP signal. The SAR studies revealed new characteristics of the GBAP signal and uncovered the most potent quorum sensing activator in E. faecalis known to date. [ABSTRACT FROM AUTHOR]

Solid-phase peptide synthesis (SPPS) is used to create peptidomimetics in which one of the backbone amide C-O bonds is replaced by a four-membered oxetane ring. The oxetane containing dipeptide building blocks are made in three steps in solution, then integrated into peptide chains by conventional Fmoc SPPS. This methodology is used to make a range of peptides in high purity including backbone modified derivatives of the nonapeptide bradykinin and Met- and Leu-enkephalin. [ABSTRACT FROM AUTHOR]

A new synthetic approach for introducing N-capping groups onto peptides attached to a solid support, combining aminocarbonylation under mild conditions using a palladacycle precatalyst and solid-phase peptide synthesis, is reported. The use of a silacarboxylic acid as an in situ CO-releasing molecule allowed the reaction to be performed in a single vial. The method also enables versatile substitution of side chains, side-chain-to-side-chain cyclizations, and selective [13C] acyl labeling of modified peptides. [ABSTRACT FROM AUTHOR]

Theonellapeptolide Id is a tridecapeptide containing a 37-membered lactone, originally isolated from the marine sponge Theonella swinhoei. In addition to moderate cytotoxicity, immunosuppressive activity had been reported for this natural cyclodepsipeptide. However, the synthetic material to verify its unique biological activity has not been available thus far. In this study, the first total synthesis of theonellapeptolide Id has been performed by solid phase peptide synthesis, and the biological activity has been confirmed in comparison with cyclosporin A. [ABSTRACT FROM AUTHOR]

The first chemical synthesis of nuclear protein HMGA1a via Ser/Thr ligation is reported. Notably, Hmb (2-hydroxy-4-methoxybenzyl) exhibits crucial improvement of both the difficult coupling during solid phase peptide synthesis and the poor ligation encountered in protein synthesis. These efforts led to preparation of HMGA1a analogs with well-defined phosphorylation and methylation patterns (9 synthetic proteins in total), thus overcoming the heterogeneous and combinatory problems inherent to protein post-translational modifications (PTMs), and facilitating the study of the regulatory roles of such PTMs. [ABSTRACT FROM AUTHOR]

An N-sulfanylethylaminooxybutyramide (SEAoxy) has been developed as a novel thioester equivalent for native chemical ligation. SEAoxy peptide was straightforwardly synthesized by conventional Fmoc solid-phase peptide synthesis without a problem. Moreover, SEAoxy peptide could be directly applied to native chemical ligation owing to the intramolecular N-to-S acyl shift that releases the peptide-thioester in situ. This methodology was successfully applied to the synthesis of two bioactive peptides. [ABSTRACT FROM AUTHOR]

An efficient N-linked glycosylation reaction between glycosylamines and p-nitrophenyl thioester peptides has been developed. The reaction conditions are mild and compatible with the C-terminal free carboxylic acid group and the unprotected N-linked sialyloligosaccharide. By means of this convergent strategy, a versatile N-glycopeptide fragment containing an N-terminal Thz and a C-terminal thioester was readily prepared, which is available for the synthesis of long glycopeptides and glycoproteins using the protocol of native chemical ligation. [ABSTRACT FROM AUTHOR]

A synthesis of gombamide A (1) using N-terminal peptide extension, oxidative disulfide bond formation, and late-stage 4-hydroxystyrylamide installation has been achieved. This divergent method was also utilized to synthesize several gombamide A derivatives with modification to the 4-hydroxystyrylamide via cyclic peptide 2. The natural product and four derivatives were found to be devoid of Na+/K+-ATPase activity at 10 μM. In addition, the compounds were not cytotoxic at 10 μM against a panel of cancer cells. [ABSTRACT FROM AUTHOR]

N-Sulfanylethylcoumarinyl amide (SECmide) peptide, which was initially developed for use in the fluorescence-guided detection of promoters of N-S acyl transfer, was successfully applied to a facile and side reaction-free protocol for N-S acyl-transfer-mediated synthesis of peptide thioesters. Additionally, 4-mercaptobenzylphosphonic acid (MBPA) was proven to be a useful catalyst for the SECmide or N-sulfanylethylanilide (SEAlide)-mediated NCL reaction. [ABSTRACT FROM AUTHOR]

An optimized protocol for the masking of α-ketoacids with acid-labile cyclic acetal protecting groups is reported. Unlike prior approaches, these new conditions allow the synthesis of protected α-ketoacids bearing aromatic, hindered alkyl, and protected polar side chains. Attachment to a Wang-type linker and solid support provides a resin that delivers fully unprotected C-terminal peptide α-ketoacids upon resin cleavage. These peptides are the key starting materials for chemical protein synthesis using the α-ketoacid-hydroxylamine ligation. [ABSTRACT FROM AUTHOR]

Reversible attachment of solubilizing tags to hydrophobic peptides to facilitate their purification and ligation is an essential yet challenging task in chemical protein synthesis. The efficient palladium-assisted removal of the solubilizing tag linked to the Cys side chain is reported. The strategy was applied for the efficient preparation of histone protein H4 from two fragments via one-pot operation of ligation, removal of the solubilizing tag, and desulfurization. [ABSTRACT FROM AUTHOR]

Peptides and peptidomimetics with a C-terminal boronic acid group have prolific applications in numerous fields of research, but their synthetic accessibility remains problematic. A convenient, high yield synthesis of peptide-boronic acids on a solid support is described here, using commercially available 1-glycerol polystyrene resin. The method is compatible with Fmoc chemistry and offers a versatile approach to aryl and alkyl aminoboronic acids without additional purification steps. [ABSTRACT FROM AUTHOR]

Triptycenes have been shown to bind nucleic acid three-way junctions, but rapid and efficient methods to diversify the triptycene core are lacking. An efficient synthesis of a 9-substituted triptycene scaffold is reported that can be used as a building block for solid-phase peptide synthesis and rapid diversification. The triptycene building block was diversified to produce a new class of tripeptide-triptycenes, and their binding abilities toward d(CAG)∙(CTG) repeat junctions were investigated [ABSTRACT FROM AUTHOR]

The Fmoc-based solid phase synthesis of C-terminal cysteine-containing peptides is problematic, due to side reactions provoked by the pronounced acidity of the Cα proton of cysteine esters. We herein describe a general strategy consisting of the postsynthetic introduction of the C-terminal Cys through a key chemoselective native chemical ligation reaction with N-Hnb-Cys peptide crypto-thioesters. This method was successfully applied to the demanding peptide sequences of two natural products of biological interest, giving remarkably high overall yields compared to that of a state of the art strategy. [ABSTRACT FROM AUTHOR]

The design, synthesis and utilization of an efficient acetamidomethyl derived resin for the peptide synthesis is presented using established Fmoc and Boc protocols via side chain anchoring. Cleavage of the target peptide from the resin is performed using carboxymethylsulfenyl chloride under mild conditions which gave in situ thiol-sulfenyl protection of the cysteine residues. The utility of the resin is successfully demonstrated through applications to the syntheses of model peptides and natural products Riparin 1.1 and Riparin 1.2. [ABSTRACT FROM AUTHOR]

A practical and efficient methodology for the chemical synthesis of peptides/proteins using a one-pot/sequential ligation is described. It features the use of photocleavable S-protection on an N-sulfanylethylaniline moiety. Removal of the S-protecting ligated materials under UV irradiation provides a readily usable mixture for subsequent native chemical ligation. [ABSTRACT FROM AUTHOR]

The design, synthesis and utilization of an efficient acetamidomethyl derived resin for the peptide synthesis is presented using established Fmoc and Boc protocols via side chain anchoring. Cleavage of the target peptide from the resin is performed using carboxymethylsulfenyl chloride under mild conditions which gave in situ thiol-sulfenyl protection of the cysteine residues. The utility of the resin is successfully demonstrated through applications to the syntheses of model peptides and natural products Riparin 1.1 and Riparin 1.2. [ABSTRACT FROM AUTHOR]

A method for site- and stereoselective peptide modification using a cyclic sulfamidate scaffold containing peptides is described. A peptide synthesis strategy allowing the rapid generation of mixed α/β-peptides incorporating a sulfamidate residue, derived from 2-methylisoserine, has been generalized. The unique electrophilic nature of this scaffold for nucleophilic substitution at a quaternary center with total inversion of its configuration, which was demonstrated computationally, allows for site-selective conjugation with various nucleophiles, such as anomeric thiocarbohydrates and pyridines. This strategy provides rapid access to complex thioglyco-α/β-conjugates and charged α/β-peptides. [ABSTRACT FROM AUTHOR]

Azopeptides possess an imino ureaas an amino amide surrogate inthe sequence. Azopeptides were synthesized by oxidation of aza-glycineresidues and employed in pericyclic chemistry. Diels–Aldercyclizations and Alder–ene reactions on azopeptides enabledconstruction of constrained aza-pipecolyl and reactive aza-allylglycylresidues. X-ray crystallographic analyses of azopeptide 16aand azapeptides 30aand 35aprovided insightinto imino urea configuration and conformational affects of cycloalkaneside chains at the semicarbazide α- and β-nitrogen, respectively. [ABSTRACT FROM AUTHOR]

A concise synthetic pathway yieldingto hydrophobic α,α-disubstituteddisilylated amino acids based on a hydrosilylation reaction is described.As a first example of utilization in solid-phase peptide synthesis,TESDpg was introduced in replacement of Aib in an alamethicin sequence,leading to analogues with modified physicochemical properties andconserved helical structures. This study highlights the potentialof these new amino acids as tools for peptide modulation. [ABSTRACT FROM AUTHOR]

6-(3,5-Bis(trifluoromethyl)phenyl)-1H,4H-2a 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. [ABSTRACT FROM AUTHOR]

A simplified analog (WU-07047) of the selective Gaq/11 inhibitor YM-254890 has been synthesized, and an initial probe of its activity conducted. In the analog, the two peptide-based linkers in the cyclic YM-254890 have been replaced with hydrocarbon chains. This enables a convergent approach to the synthesis of the analog. Biochemical assays showed that while the simplified analog is not as potent as YM-254890, it does still inhibit Gq. [ABSTRACT FROM AUTHOR]

Bogorol A [(E)-1], a potent antibiotic against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp., possesses a thermodynamically unfavored (E)-2-amino-2-butenamide within its linear dodecapeptide sequence. The highly efficient total synthesis of natural (E)-isomer (E)-1 and its artificial (Z)-isomer (Z)-1 by employing a full solid-phase strategy is reported. The (E)- and (Z)-2-amino-2-butenamide moieties were stereoselectively constructed by applying traceless Staudinger ligation on the resin. Interestingly, (E)- and (Z)-1 showed comparable antimicrobial activity (MIC = 4 μg/mL). [ABSTRACT FROM AUTHOR]

Nativechemical ligation (NCL) performed without resorting to theuse of thiol additives was demonstrated to be an efficient and effectiveprocedure for synthesizing Cys-rich peptides. This method using tris(2-carboxyethyl)phosphine(TCEP) as a reducing agent facilitates the ligation reaction evenat the Thr-Cys or Ile-Cys site and enables one-pot synthesis of Cys-richpeptides throughout NCL and oxidative folding. [ABSTRACT FROM AUTHOR]

Bridged peptides including stapledpeptides are attractive toolsfor regulating protein–protein interactions (PPIs). An effectivesynthetic methodology in a heterogeneous system for the preparationof these peptides using olefin metathesis and hydrogenation of protectedpeptides with a long aliphatic chain anchor is reported. [ABSTRACT FROM AUTHOR]

Streamlinedaccess to S-glycosylated Fmoc-aminoacids was developed. The process provides diverse glycosylated modifiedamino acids in high yield and stereoselectivity taking advantage ofthe in situgeneration of a glycosylthiolate obtainedfrom carbohydrate acetates in a few steps. Mild basic conditions makethe conjugation reaction compatible with Fmoc-iodo-amino acids. Tovalidate the strategy the glycosylated building blocks were used forSPPS and the unprecedented incorporation of a long thio-oligosaccharideto the peptide chain was demonstrated. [ABSTRACT FROM AUTHOR]

A highlyaggregating elastin peptide was prepared efficiently usinga high pressure–liquid phase synthesis approach assisted bya soluble tag strategy. Two standard syringes were connected to eachother to construct a reactor. This simple reactor was used to applyhigh pressure to the highly viscous reaction mixture thereby maintainingits fluidity. The reactions were completely inhibited due to aggregationwhen conducted in a standard flask reactor, whereas our high pressureapproach accelerated the couplings to realize complete conversionwithin 5–7 min. All steps were conducted at 0.10 M concentration,affording grams of the desired product. [ABSTRACT FROM AUTHOR]

Tritylation usingtrityl alcohol (Trt–OH) in 1,1,1,3,3,3-hexafluoro-2-propanol(HFIP) is a convenient and efficient procedure that can offer S-protection of the Cys located in fully unprotected peptides.The procedure simply requires Trt–OH and HFIP to selectivelypromote S-tritylation in the presence of peptidenucleophilic functionalities. [ABSTRACT FROM AUTHOR]

A new synthetic methodfor peptide thioesters is described usingFmoc solid-phase peptide synthesis (Fmoc-SPPS). This method employsa novel enamide motif to facilitate irreversible intramolecular N-to-Sacyl migration, which can efficiently afford the desired peptide thioesters(3 h, 30 °C) under the final trifluoroacetic acid (TFA) cleavageconditions. The acyl-transfer-mediated approach for synthesis of peptidethioesters tolerated different C-terminal residues and was used tosynthesize human C–C motif chemokine 11 (hCCL11) via nativechemical ligation. [ABSTRACT FROM AUTHOR]

Thesynthesis of novel oxetanyl peptides, where the amide bondis replaced by a non-hydrolyzable oxetanylamine fragment, is reported.This new class of pseudo-dipeptides with the same H-bond donor/acceptorpattern found in proteins expands the repertoire of peptidomimetics. [ABSTRACT FROM AUTHOR]

A concisesynthesis of peptides that contain E- or Z-dehydroisoleucine (ΔIle) residues isreported. The key reaction is an unusual antidehydrationof β-tert-hydroxy amino acid derivatives thatis mediated by the Martin sulfurane. A subsequent tandem Staudingerreduction–O → N acyl transfer process forges an amidebond to the ΔIle residue with minimal E/Zalkene isomerization. Density functional calculationsattribute the stereospecific dehydration to a highly asynchronousE2 antiprocess. [ABSTRACT FROM AUTHOR]

Peptides containingN2-acyl piperazic or 1,6-dehydropiperazicacids can be formed efficiently via a novel multicomponent reactionof 1,4,5,6-tetrahydropyridazines, isocyanides, and carboxylicacids. Remarkably, the reaction’s induced intramolecularitycan enable the regiospecific formation of products with N2-acyl piperazicacid, which counters the intrinsic and troublesome propensity forpiperazic acids to react at N1 in acylations. The utility of the methodologyis demonstrated in the synthesis of the bicyclic core of the interleukin-1βconverting enzyme inhibitor, Pralnacasan. [ABSTRACT FROM AUTHOR]

An ionic liquid-supportedsynthetic method for the constructionof glycopeptides in high yields is reported. This method avoids theuse of large excesses of reagents and chromatographic purificationand, therefore, represents a useful addition to existing approachesfor the ionic liquid-supported synthesis of oligosaccharides and peptides. [ABSTRACT FROM AUTHOR]

Describedhere is the design, synthesis, and conformational analysisof cyclic tetrapeptides (CTPs) with α3γ architecturecontaining a furan-based locked Z-vinylogous aminoacid (Vaa). This unnatural amino acid locks into a γ-turn thatinduces type IαRS-turn in the CTPs. Stabilized bya 13-membered intramolecular H-bond, these CTPs show robust conformationin water and aprotic solvent irrespective of the sequence of tripeptideconsisting of α-amino acids used. [ABSTRACT FROM AUTHOR]

Contraryto other studies, here we describe cysteine (Cys) pseudoproline-containingpeptides with short deprotection times in TFA. The deprotection timesfell in the same range as other protecting groups commonly used inSPPS (e.g., 1–3 h). Moreover, when using Cys pseudoprolinesas peptide macrocyclization-enhancing moieties a considerable reductionin reaction time was observed compared to a peptide containing tritylprotected Cys. [ABSTRACT FROM AUTHOR]

Duringautomated solid-phase peptide synthesis, failure sequences were cappedwith acetic anhydride. After synthesis, a polymerizable methacrylamidetag was attached to the full-length sequences. Peptide purificationwas then achieved by polymerizing the full-length sequences, washingaway impurities, and cleaving the peptide product from the polymer. [ABSTRACT FROM AUTHOR]

A series of improvements to the standardsolid phase peptide synthesis(SPPS) process allowing for significant gains in product purity alongwith only a 4 min standard cycle time and a 90% reduction in totalwaste produced is reported. For example, syntheses of the well-known 65–74acyl carrier protein (ACP) and 1–42β-amyloid peptides were accomplished with 93 and 72% purity(UPLC–MS) in only 44 and 229 min, respectively. [ABSTRACT FROM AUTHOR]

An efficient methodhas been developed for the direct amidificationof carboxylic acids via sulfinylamides preformed in situ by the reactionof pure amines with prop-2-ene-1-sulfinyl chloride. The method canbe applied to aliphatic acids, including pivalic acid, aromatic acids,and primary and secondary amines. It is compatible with acids bearingunprotected alcohol, phenol, and ketone moieties and applicable tothe synthesis of peptides. It does not induce their α-epimerization. [ABSTRACT FROM AUTHOR]