Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers.

ABSTRACT: Copper-mediated coupling between alkynes to generate a structurally rigid, linear 1,3-diyne linkage has been known for over a century. However, the mechanistic requirement to simultaneously maintain CuI and an oxidant has limited its practical utility, especially for complex functional molecules in aqueous solution. We find that addition of a specific bpy-diol ligand protects unprotected peptides from CuII -mediated oxidative damage through the formation of an insoluble CuII gel which solves the critical challenge of applying Glaser coupling to substrates that are degraded by CuII . The generality of this method is illustrated through the conjugation of a series of polar and nonpolar labels onto a fully unprotected GLP-1R agonist through a linear 7?Å diynyl linker.

SUBMITTER: Silvestri AP

PROVIDER: S-EPMC5708120 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers.

Silvestri Anthony P AP Cistrone Philip A PA Dawson Philip E PE

Angewandte Chemie (International ed. in English) 20170721 35

Copper-mediated coupling between alkynes to generate a structurally rigid, linear 1,3-diyne linkage has been known for over a century. However, the mechanistic requirement to simultaneously maintain Cu<sup>I</sup> and an oxidant has limited its practical utility, especially for complex functional molecules in aqueous solution. We find that addition of a specific bpy-diol ligand protects unprotected peptides from Cu<sup>II</sup> -mediated oxidative damage through the formation of an insoluble Cu< ...[more]

PMID: 28685936

Similar Datasets

From Ugi Multicomponent Reaction to Linkers for Bioconjugation.

Project description:Bioconjugation is a key approach for the development of novel molecular entities with clinical applications. The biocompatibility and specificity of biomolecules such as peptides, proteins, and antibodies make these macromolecules ideal carriers for selective targeted therapies. In this context, there is a need to develop new molecular units that cover the requirements of the next generation of targeted pharmaceuticals. Here, we present the design and development of a versatile and stable linker based on a N-alkylated ?,?-dialkyl dipeptide for bioconjugation, with a particular focus on antibody-drug conjugates (ADCs). Starting with the well-known Ugi multicomponent reaction, the convenient chemical modification of the prepared adducts allowed us the obtention of versatile bifunctional linkers for bioconjugation. A conjugation strategy was tested to demonstrate the efficiency of the linker. In addition, a novel cytotoxic anti-HER2 ADC was prepared using the Ugi-linker approach.

| S-EPMC7144135 | biostudies-literature

Rigid Peptide Macrocycles from On-Resin Glaser Stapling.

Project description:Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 α-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.

| S-EPMC6097620 | biostudies-literature

Mechanistic investigation and further optimization of the aqueous Glaser-Hay bioconjugation.

Project description:The Glaser-Hay bioconjugation has recently emerged as an efficient and attractive method to generate stable, useful bioconjugates with numerous applications, specifically in the field of therapeutics. Herein, we investigate the mechanism of the aqueous Glaser-Hay coupling to better understand optimization strategies. In doing so, it was identified that catalase is able to minimize protein oxidation and improve coupling efficiency, suggesting that hydrogen peroxide is produced during the aqueous Glaser-Hay bioconjugation. Further, several new ligands were investigated to minimize protein oxidation and maximize coupling efficiency. Finally, two novel strategies to streamline the Glaser-Hay bioconjugation and eliminate the need for secondary purification have been developed.

| S-EPMC6482449 | biostudies-literature

An aromatic Glaser-Hay reaction.

Project description:A general method for copper-catalyzed deprotonative dimerization of arenes by employing oxygen as the terminal oxidant has been developed. Electron-rich and electron-poor heterocycles as well as electron-poor arenes are reactive. The method is tolerant to functionalities such as nitro, cyano, dialkylamino, and ester groups.

| S-EPMC2791693 | biostudies-literature

Co (II) Boron Imidazolate Framework with Rigid Auxiliary Linkers for Stable Electrocatalytic Oxygen Evolution Reaction.

Project description:Metal-organic frameworks (MOFs) have significant potential for practical application in catalysis. However, many MOFs are shown to be sensitive to aqueous solution. This severely limits application of MOFs in electrocatalytic operations for energy production and storage. Here, a Co (II) boron imidazolate framework CoB(im)4(ndc)0.5 (BIF-91, im = imidazolate, ndc = 2,6-naphthalenedicarboxylate) that is rationally designed and successfully tested for electrocatalytic application in strong alkaline (pH ≈ 14) solution is reported. In such a BIF system, the inherent carboxylate species segment large channel spaces into multiple domains in which each single channel is filled with ndc ligands through the effect of zeolite channel confinement. These ligands, with strong C-H···π interaction, act as a rigid auxiliary linker to significantly enhance the structural stability of the BIF-91 framework. Additionally, the π-conjugated effect in BIF-91 stabilizes dopant Fe (III) at the atomic scale to construct Fe-immobilized BIF-91 (Fe@BIF-91). Due to the synergistic effect between Fe (III) guest and Co (II) in the framework, the Fe@BIF-91 acts as an active and stable electrocatalyst for the oxygen evolution reaction in alkaline solution.

| S-EPMC6498129 | biostudies-other

A Simple and Practical Bis-N-Heterocyclic Carbene as an Efficient Ligand in Cu-Catalyzed Glaser Reaction.

Project description:Conjugated diyne derivatives are important scaffolds in modern organic synthetic chemistry. Using the Glaser reaction involves the coupling of terminal alkynes which can efficiently produce conjugated diyne derivatives, while the use of a stoichiometric amount of copper salts, strong inorganic base, and excess oxidants is generally needed. Developing an environmentally friendly and effective method for the construction of symmetrical 1,3-diynes compounds by Glaser coupling is still highly desirable. In this study, we present an economical method for the production of symmetric diynes starting from various terminal acetylenes in a Glaser reaction. A simple and practical bis-N-heterocyclic carbene ligand has been introduced as efficient ligands for the Cu-catalyzed Glaser reaction. High product yields were obtained at 100 °C for a variety of substrates including aliphatic and aromatic terminal alkynes and differently substituted terminal alkynes including the highly sterically hindered substrate 2-methoxy ethynylbenzene or 2-trifluoromethyl ethynylbenzene and a series of functional groups, such as trifluoromethyl group, ester group, carboxyl group, and nitrile group. The established protocol is carried out in air under base-free condition and is operationally simple. These research work suggest that bis-N-heterocyclic carbene could also an appealing ligand for Glaser reaction and provide a reference for the preparation of symmetric 1,3-diynes in industrial filed.

| S-EPMC10343847 | biostudies-literature

Benzotriazole as an Efficient Ligand in Cu-Catalyzed Glaser Reaction.

Project description:Benzotriazole has been established as an efficient ligand in Cu-catalyzed cross-coupling of terminal alkynes to form 1,3-dialkynes using CuI as the catalyst and K2CO3 as the base at room temperature in an open round-bottom flask. The established protocol has the following notable advantages: simple to handle, easy work-up, mild reaction condition, high substrate scope, requirement of less quantity of ligand and also Cu-catalyst, less expensive, and high reaction yield.

| S-EPMC6648008 | biostudies-literature

Rapid and robust cysteine bioconjugation with vinylheteroarenes.

Project description:Methods for residue-selective and stable modification of canonical amino acids enable the installation of distinct functionality which can aid in the interrogation of biological processes or the generation of new therapeutic modalities. Herein, we report an extensive investigation of reactivity and stability profiles for a series of vinylheteroarene motifs. Studies on small molecule and protein substrates identified an optimum vinylheteroarene scaffold for selective cysteine modification. Utilisation of this lead linker to modify a number of protein substrates with various functionalities, including the synthesis of a homogeneous, stable and biologically active antibody-drug conjugate (ADC) was then achieved. The reagent was also efficient in labelling proteome-wide cysteines in cell lysates. The efficiency and selectivity of these reagents as well as the stability of the products makes them suitable for the generation of biotherapeutics or studies in chemical biology.

| S-EPMC8261766 | biostudies-literature

Structurally robust biological networks.

Project description:BackgroundThe molecular circuitry of living organisms performs remarkably robust regulatory tasks, despite the often intrinsic variability of its components. A large body of research has in fact highlighted that robustness is often a structural property of biological systems. However, there are few systematic methods to mathematically model and describe structural robustness. With a few exceptions, numerical studies are often the preferred approach to this type of investigation.ResultsIn this paper, we propose a framework to analyze robust stability of equilibria in biological networks. We employ Lyapunov and invariant sets theory, focusing on the structure of ordinary differential equation models. Without resorting to extensive numerical simulations, often necessary to explore the behavior of a model in its parameter space, we provide rigorous proofs of robust stability of known bio-molecular networks. Our results are in line with existing literature.ConclusionsThe impact of our results is twofold: on the one hand, we highlight that classical and simple control theory methods are extremely useful to characterize the behavior of biological networks analytically. On the other hand, we are able to demonstrate that some biological networks are robust thanks to their structure and some qualitative properties of the interactions, regardless of the specific values of their parameters.

| S-EPMC3125314 | biostudies-literature

A Chemoselective Rapid Azo-Coupling Reaction (CRACR) for Unclickable Bioconjugation.

Project description:Chemoselective modification of complex biomolecules has become a cornerstone of chemical biology. Despite the exciting developments of the past two decades, the demand for new chemoselective reactions with unique abilities, and those compatible with existing chemistries for concurrent multisite-directed labeling, remains high. Here we show that 5-hydroxyindoles exhibit remarkably high reactivity toward aromatic diazonium ions and this reaction can be used to chemoselectively label proteins. We have previously genetically encoded the noncanonical amino acid 5-hydroxytryptophan in both E. coli and eukaryotes, enabling efficient site-specific incorporation of 5-hydroxyindole into virtually any protein. The 5-hydroxytryptophan residue was shown to allow rapid, chemoselective protein modification using the azo-coupling reaction, and the utility of this bioconjugation strategy was further illustrated by generating a functional antibody-fluorophore conjugate. Although the resulting azo-linkage is otherwise stable, we show that it can be efficiently cleaved upon treatment with dithionite. Our work establishes a unique chemoselective "unclickable" bioconjugation strategy to site-specifically modify proteins expressed in both bacteria and eukaryotes.

| S-EPMC5861709 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data