New isocysteine building blocks and chemoselective peptide ligation

Boc-, Fmoc- and Cbz-protected isocysteine building blocks were prepared by a concise three-step procedure starting from thiomalic acid. The use of Boc/Trt-protected isocysteine provided convenient access to isocysteinyl peptides that allow the chemoselective ligation of unprotected peptide fragments in water. The pH-dependency of the isocysteine-mediated ligation was compared with that of cysteine-mediated native chemical ligation.     

BINOL-based foldamers--access to oligomers with diverse structural architectures

In this article, we report on the synthesis and conformation of a new family of aromatic oligoamide foldamers based on binaphthol (BINOL) monomers. A series of oligomers with differing chirality of the individual BINOL building blocks and mixed sequences of alternate BINOL and pyridyl building blocks has been synthesized and structurally characterized. NMR and quantum chemical calculations on the basis of ab initio MO theory were performed to obtain insight into the conformational features of these oligomers. It is shown that the combination of these inherently chiral aromatic building blocks provides a novel access to a wide variety of conformationally ordered synthetic oligomers with diverse and dazzling structural architectures distinct from those classically observed.     

Template assembled synthetic proteins: Condensation of a multifunctional peptide to a topological template via chemoselective ligation

A chemoselective ligation via oxime bond formation is used for the chemical synthesis of template assembled peptides according to the TASP (Template Assembled Synthetic Proteins) approach. Aminooxyacetylation of the multifunctional partial sequence Lys- Arg- Asp- Ser of lactoferrin and subsequent condensation in aqueous solution with a topological template containing four selectively addressable aldehyde functions as attachment sites gives readily access to the TASP molecule.     

On-resin peptide ligation via C-terminus benzyl ester

Here, we reported a new approach of on-resin peptide ligation using C-terminal benzyl ester as the stabilized precursor of thioester, which enables both N-terminal elongation and C-terminal peptide ligation on a Rink Amide resin.     

On-resin peptide ligation via C-terminus benzvl ester

Here, we report a new approach of on-resin peptide ligation using C-terminal benzyl ester as the stabilized precursor of thioester, which enables both N-terminal elongation and C-terminal peptide ligation on a Rink Amide resin. On-resin native chemical ligation and auxiliary-assisted peptide ligation were successfully achieved. This method is compatible to both protected and unprotected peptide fragments and has potential application in poor water-soluble peptide ligation.     

Chemical synthesis of Ub-AMC via ligation of peptide hydrazides

The C-terminal conjugate of ubiquitin with 7-amino-4-methylcoumarin (Ub-AMC) is an important probe for fluorescencebased analysis of deubiquitinating enzyme (DUB) activity. It is important to develop more efficient methods for the preparation of Ub-AMC because the currently available technology is still expensive for scaled-up production. In the present work we report an efficient strategy for total chemical synthesis of Ub-AMC through ligation of peptide hydrazides. Three peptide segments are assembled via N-to-C sequential ligation and the resulting product is converted to Ub-AMC via TCEP-mediated desulfurization. The synthetic Ub-AMC is shown to have expected biological functions throug     

多肽酰肼连接法合成C端香豆素修饰的泛素

C端用香豆素修饰的泛素分子（Ub-AMC）是研究蛋白质泛素化过程的重要探针.该探针分子的制备目前主要依靠生物表达结合化学修饰的方法,合成效率较低.本文使用多肽酰肼连接反应,发展出化学全合成Ub-AMC分子的新路线.该方法通过N到C顺序两次连接实现了目标分子的组装,再通过自由基脱硫反应得到天然结构的Ub-AMC分子,有望实现较大量的合成.通过酶学活性实验,证实了通过新方法合成的Ub-AMC具有预期的生物活性.     

Glycoconjugate and oligosaccharide mimetics by chemoselective ligation

Different approaches for the synthesis of neoglycoconjugates, exploiting chemoselective ligation procedures, are reported. Based on the reaction of the carbonyl group of ketones or aldehydes (including the anomeric centre of the sugar) with strong nucleophiles such as hydroxylamino- or hydrazino-derivatives, or on the addition of sulfidryl groups to a variety of electrophiles, these procedures afford bioactive neo-glycoconjugates avoiding protection–deprotection and activation steps. Conjugation of two copies of the C-saccharide analogue of the T_n epitope with the immunogenic peptide OVA^(327–339) by way of chemoselective ligation, afforded a neo-glycopeptide capable of inducing in vivo B- and T-cell response to tumours exposing T_n epitope. To cite this article: F. Peri et al., C. R. Chimie 6 (2003).     

Synthesis of macrocyclic peptide nucleic acid derivatives via intramolecular chemical ligation

Macrocyclic peptide nucleic acids can be obtained by direct or indirect intramolecular cyclisation of N-terminal cysteine functionalised PNA-thioesters     

Multimeric cyclic RGD peptides as potential tools for tumor targeting: solid-phase peptide synthesis and chemoselective oxime ligation

The alpha v beta 3 integrin receptor plays an important role in human metastasis and tumor-induced angiogenesis. Targeting this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Solid-phase peptide synthesis of multimeric cyclo(-RGDfE-)-peptides is described, which offer the possibility of enhanced integrin targeting due to polyvalency effects. These peptides contain an aminooxy group for versatile chemoselective oxime ligation. Conjugation with para-trimethylstannylbenzaldehyde results in a precursor for radioiododestannylation, which would allow them to be used as potential tools for targeting and imaging alpha v beta 3-expressing tumor cells. The conjugates were obtained in good yield without the need of a protection strategy and under mild conditions.     

A chemoselective approach for the accelerated synthesis of well-defined dendritic architectures

A chemoselective and layered growth approach has been developed for the synthesis of dendrimers, combining Click chemistry with traditional esterification/etherification reactions, without the need for activation steps and with excellent overall yields.     

An efficient peptide ligation using azido-protected peptides via the thioester method

Azido-protected Fmoc-Lys-OH (Fmoc-Lys(N₃)-OH) was synthesized from Fmoc-Lys-OH by the copper(II)-catalyzed diazo transfer method, and introduced to a peptide by the ordinary Fmoc-based solid-phase peptide synthesis. This azido peptide could be condensed with a peptide thioester by the Ag⁺-free thioester method without any significant side reactions. The azido group was easily reduced to an amino group by Zn powder after peptide condensation.     

First aldehyde-functionalized poly(2-oxazoline)s for chemoselective ligation

A protected aldehyde-functionalized 2-oxazoline, 2-[3-(1,3)-dioxolan-2-ylpropyl]-2-oxazoline (DPOx), was synthesized from commercially available compounds in high yields. The polymerization of DPOx with different initiators proceeds via a living ionic mechanism; thus, the polymers were of low polydispersity and the degree of polymerization could be precisely adjusted. Copolymerization with 2-methyl-2-oxazoline gave water-soluble statistical copolymers. Hydrolysis of the homo- and copolymers resulted in well-defined, aldehyde-bearing poly(2-oxazoline)s. The aldehyde side functions reacted quantitatively with an amino-oxy compound to form the corresponding oxime.     

Defect-free polymer multilayers prepared via chemoselective immobilization

In this paper, we investigated electrochemical properties of polymer multilayers on gold substrates using impedance spectroscopy. The multilayer was prepared by chemoselective ligation between aldehyde- and oxyamine-functionalized polymers via a layer-by-layer approach. The impedance spectra in a buffer solution in the absence of redox species revealed the formation of highly impermeable and defect-free films. The dielectric thickness of the polymer film, which is proportional to the reciprocal of capacitance, linearly increased as the number of deposition layer increased. The defect area of the polymer multilayer was obtained using the faradaic impedance with redox species. The surface coverage of eight polymer layers was determined to be 99.99%. Thus, the layer-by-layer deposition via chemoselective ligation offers a new way to prepare a highly insulating and defect-free polymer layer with finely tunable capacitance as a function of the number of deposition layers.     

Convergent synthesis of peptide conjugates using dehydroalanines for chemoselective ligations

[reaction: see text]. Protein and peptide conjugates such as glycopeptides, prenylated peptides, and lipopeptides play essential roles in biology. A rapid and convergent entry into a variety of these compounds is described. The methodology involves the introduction of a dehydroalanine into peptides and subsequent chemoselective conjugate addition of an appropriate thiolate nucleophile, including farnesylthiolate or thioglycosides.     

A "traceless" Staudinger ligation for the chemoselective synthesis of amide bonds

[reaction: see text] Here we report a novel modification of our previously reported "Staudinger ligation" that generates an amide bond from an azide and a specifically functionalized phosphine. This method for the selective formation of an amide bond, which does not require the orthogonal protection of distal functional groups, should find general utility in synthetic and biological chemistry.     

Stereoretentive synthesis and chemoselective amide-forming ligations of C-terminal peptide alpha-ketoacids

C-Terminal peptide cyanosulfur ylides are readily converted to C-terminal peptide alpha-ketoacids, poised for chemoselective amide-forming reactions with hydroxylamines. These easily prepared and bench stable ylides are quickly and selectively oxidized with aqueous Oxone without the need for protection of most peptide side chains and with minimal epimerization. This approach offers the first method for preparing enantiomerically enriched, side chain unprotected alpha-ketoacids.     

A chemoselective desulfurization method via homogeneous nickel catalysis

Isopropylmagnesium bromide in the presence of bis-(triphenylphosphino)- nickel(II) chloride reduces vinyl sulfides stereospecifically to the corresponding olefins without overreduction - a process which serves as a key step in the synthesis of the sex pheromone of the Douglas fir tussock moth.     

Effective synthesis of cyclic peptide yunnanin C and analogues via Ser/Thr ligation (STL)-mediated peptide cyclization

Cyclic peptide yunnanin C isolated from the root of Stellaria yunnanensis was efficiently synthesized in which the linear peptide was prepared by Boc-SPPS and the cyclization was realized by serine/threonine ligation (STL)-mediated cyclization. In addition, nine yunnanin C analogues, including mutations of Tyr7Gly, Tyr7Val, Tyr7Pro, Tyr7Phe, Ser1Thr, Pro2Val, Gly5Pro, Phe6Ala and Ile4Ala, were prepared in the same fashion. Here, we demonstrated that STL-mediated peptide cyclization could be an effective approach to construct cyclic peptides. Except that proline at the C-terminus could retard the cyclization process, cyclization of yunnanin C analogues with various C-terminal amino acids proceeded with fast cyclization rate (<4 h) and only trace amount of dimers (<5%) at a working concentration of 5 mM.     

By-design molecular architectures via alkyne metathesis

Shape-persistent purely organic molecular architectures have attracted tremendous research interest in the past few decades. Dynamic Covalent Chemistry (DCvC), which deals with reversible covalent bond formation reactions, has emerged as an efficient synthetic approach for constructing these well-defined molecular architectures. Among various dynamic linkages, the formation of ethynylene linkages through dynamic alkyne metathesis is of particular interest due to their high chemical stability, linearity, and rigidity. In this review, we focus on the synthetic strategies of discrete molecular architectures (e.g., macrocycles, molecular cages) containing ethynylene linkages using alkyne metathesis as the key step, and their applications. We will introduce the history and challenges in the synthesis of those architectures via alkyne metathesis, the development of alkyne metathesis catalysts, the reported novel macrocycle structures, molecular cage structures, and their applications. In the end, we offer an outlook of this field and remaining challenges.

The recent synthesis of novel shape-persistent 2D and 3D molecular architectures via alkyne metathesis is reviewed and the critical role of catalysts is also highlighted.