-
Chembiochem : a European Journal of... Oct 2022Chemical protein synthesis has proven to be a powerful tool to access homogenously modified proteins. The chemical synthesis of nanobodies (Nb) would create...
Chemical protein synthesis has proven to be a powerful tool to access homogenously modified proteins. The chemical synthesis of nanobodies (Nb) would create possibilities to design tailored Nbs with a range of chemical modifications such as tags, linkers, reporter groups, and subsequently, Nb-drug conjugates. Herein, we describe the total chemical synthesis of a 123 amino-acid Nb against GFP. A native chemical ligation- desulfurization strategy was successfully applied for the synthesis of this GFP Nb, modified with a propargyl (PA) moiety for on-demand functionalization. Biophysical characterization indicated that the synthetic GFP Nb-PA was correctly folded after internal disulfide bond formation. The synthetic Nb-PA was functionalized with a biotin or a sulfo-cyanine5 dye by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), resulting in two distinct probes used for functional in vitro validation in pull-down and confocal microscopy settings.
Topics: Alkynes; Azides; Biotin; Click Chemistry; Copper; Disulfides; Proteins; Single-Domain Antibodies
PubMed: 35920208
DOI: 10.1002/cbic.202200304 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2023Exploiting bimetallic cooperation alkali-metal manganate (II) complexes can efficiently promote oxidative homocoupling of terminal alkynes furnishing an array of...
Exploiting bimetallic cooperation alkali-metal manganate (II) complexes can efficiently promote oxidative homocoupling of terminal alkynes furnishing an array of conjugated 1,3-diynes. The influence of the alkali-metal on these C-C bond forming processes has been studied by preparing and structurally characterizing the alkali-metal tetra(alkyl) manganates [(TMEDA) Na Mn(CH SiMe ) ] and [(PMDETA) K Mn(CH SiMe ) ]. Reactivity studies using phenylacetylene as a model substrate have revealed that for the homocoupling to take place initial metalation of the alkyne is required. In this regard, the lack of basicity of neutral Mn(CH SiMe ) precludes the formation of the diyne. Contrastingly, the tetra(alkyl) alkali-metal manganates behave as polybasic reagents, being able to easily deprotonate phenylacetylene yielding [{(THF) Na Mn(C≡CPh) } ] and [(THF) Li Mn(C≡CPh) ]. Controlled exposure of [{(THF) Na Mn(C≡CPh) } ] and [(THF) Li Mn(C≡CPh) ] to dry air confirmed their intermediary in formation of 1,4-diphenyl-1,3-butadiyne in excellent yields. While the Na/Mn(II) partnership proved to be the most efficient in stoichiometric transformations, under catalytic regimes, the combination of MC≡CAr (M= Li, Na) and MnCl (6 mol %) only works for lithium, most likely due to the degradation of alkynylsodiums under the aerobic reaction conditions.
Topics: Alkynes; Sodium; Lithium; Oxidative Stress; Alkalies
PubMed: 36929782
DOI: 10.1002/chem.202300593 -
Journal of the American Chemical Society Nov 2011New additions to the bioorthogonal chemistry compendium can advance biological research by enabling multiplexed analysis of biomolecules in complex systems. Here we...
New additions to the bioorthogonal chemistry compendium can advance biological research by enabling multiplexed analysis of biomolecules in complex systems. Here we introduce the quadricyclane ligation, a new bioorthogonal reaction between the highly strained hydrocarbon quadricyclane and Ni bis(dithiolene) reagents. This reaction has a second-order rate constant of 0.25 M(-1) s(-1), on par with fast bioorthogonal reactions of azides, and proceeds readily in aqueous environments. Ni bis(dithiolene) probes selectively labeled quadricyclane-modified bovine serum albumin, even in the presence of cell lysate. We have demonstrated that the quadricyclane ligation is compatible with, and orthogonal to, strain-promoted azide-alkyne cycloaddition and oxime ligation chemistries by performing all three reactions in one pot on differentially functionalized protein substrates. The quadricyclane ligation joins a small but growing list of tools for the selective covalent modification of biomolecules.
Topics: Alkynes; Animals; Azides; Bridged-Ring Compounds; Cattle; Cyclization; Molecular Structure; Organometallic Compounds; Serum Albumin, Bovine
PubMed: 21962173
DOI: 10.1021/ja2072934 -
Molecules (Basel, Switzerland) Nov 2022Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical...
Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.
Topics: Copper; Catalysis; Azides; Triazoles; Alkynes
PubMed: 36431885
DOI: 10.3390/molecules27227784 -
Angewandte Chemie (International Ed. in... Jan 2022Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active...
Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of Pt -TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA-intercalating fluorophore-into Pt -TFOs constructs, enhanced target binding and discrimination between target and off-target sequences was achieved.
Topics: Alkynes; Click Chemistry; Coordination Complexes; DNA; Oligonucleotides; Platinum
PubMed: 34652881
DOI: 10.1002/anie.202110455 -
The Journal of Organic Chemistry Mar 2019Silyl triflate precursors to cyclic alkynes and allenes serve as valuable synthetic building blocks. We report a concise and scalable synthetic approach to prepare the...
Silyl triflate precursors to cyclic alkynes and allenes serve as valuable synthetic building blocks. We report a concise and scalable synthetic approach to prepare the silyl triflate precursors to cyclohexyne and 1,2-cyclohexadiene. The strategy involves a retro-Brook rearrangement of an easily accessible cyclohexanone derivative, followed by triflation protocols. This simple, yet controlled, method should enable the further study of strained alkynes and allenes in chemical synthesis.
Topics: Alkynes; Cyclohexenes; Molecular Structure; Organosilicon Compounds
PubMed: 30840455
DOI: 10.1021/acs.joc.8b03223 -
Molecules (Basel, Switzerland) May 2022A modular platform for the synthesis of tunable aza-oxa-based macrocycles was established. Modulations in the backbone and the side-chain functional groups have been...
A modular platform for the synthesis of tunable aza-oxa-based macrocycles was established. Modulations in the backbone and the side-chain functional groups have been rendered to achieve the tunable property. These aza-oxa-based macrocycles can also differ in the number of heteroatoms in the backbone and the ring size of the macrocycles. For the proof of concept, a library of macrocycles was synthesized with various hanging functional groups, different combinations of heteroatoms, and ring sizes in the range of 17-27 atoms and was characterized by NMR and mass spectrometry. In light of the importance of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and the significance of triazole groups for various applications, we employed the click-reaction-based macrocyclization. The competence of the synthesized macrocycles in various biomedical applications was proven by studying the interactions with the serum albumin proteins; bovine serum albumin and human serum albumin. It was observed that some candidates, based on their hanging functional groups and specific backbone atoms, could interact well with the protein, thus improving the bioactive properties. On the whole, this work is a proof-of-concept to explore the backbone- and side-chain-tunable macrocycle for different properties and applications.
Topics: Alkynes; Azides; Catalysis; Click Chemistry; Copper; Humans; Serum Albumin, Bovine; Triazoles
PubMed: 35684347
DOI: 10.3390/molecules27113409 -
Journal of the American Chemical Society Aug 2017We report an enantioselective coupling between alkynes and indoles. A Rh-hydride catalyst isomerizes alkynes to generate a metal-allyl species that can be trapped with...
We report an enantioselective coupling between alkynes and indoles. A Rh-hydride catalyst isomerizes alkynes to generate a metal-allyl species that can be trapped with both aromatic and heteroaromatic nucleophiles.
Topics: Alkynes; Catalysis; Hydrogen; Indoles; Rhodium; Stereoisomerism
PubMed: 28742333
DOI: 10.1021/jacs.7b05893 -
Molecules (Basel, Switzerland) Oct 2013The copper (I)-catalyzed alkyne azide 1,3-dipolar cycloaddition (CuAAC) or 'click' reaction, is a highly versatile reaction that can be performed under a variety of...
The copper (I)-catalyzed alkyne azide 1,3-dipolar cycloaddition (CuAAC) or 'click' reaction, is a highly versatile reaction that can be performed under a variety of reaction conditions including various solvents, a wide pH and temperature range, and using different copper sources, with or without additional ligands or reducing agents. This reaction is highly selective and can be performed in the presence of other functional moieties. The flexibility and selectivity has resulted in growing interest in the application of CuAAC in various fields. In this review, we briefly describe the importance of the structural folding of peptides and proteins and how the 1,4-disubstituted triazole product of the CuAAC reaction is a suitable isoster for an amide bond. However the major focus of the review is the application of this reaction to produce peptide conjugates for tagging and targeting purpose, linkers for multifunctional biomacromolecules, and reporter ions for peptide and protein analysis.
Topics: Alkynes; Azides; Click Chemistry; Copper; Peptides; Proteins
PubMed: 24284482
DOI: 10.3390/molecules181113148 -
Nanotheranostics 2022Surface enhanced Raman scattering (SERS) is proving to be a useful tool for biomedical imaging. However, this imaging technique can suffer from poor signal-to-noise...
Surface enhanced Raman scattering (SERS) is proving to be a useful tool for biomedical imaging. However, this imaging technique can suffer from poor signal-to-noise ratio, as the complexity of biological tissues can lead to overlapping of Raman bands from tissues and the Raman reporter molecule utilized. Herein we describe the synthesis of triple bond containing Raman reporters that scatter light in the biological silent window, between 1750 cm and 2750 cm. Our SERS nanoprobes are comprised of uniquely designed Raman reporters containing either alkyne- or cyano-functional groups, enabling them to be readily distinguished from background biological tissue. We identify promising candidates that eventually can be moved forward as Raman reporters in SERS nanoparticles for highly specific contrast-enhanced Raman-based disease or analyte detection in biological applications.
Topics: Alkynes; Gold; Nanoparticles; Spectrum Analysis, Raman
PubMed: 34976577
DOI: 10.7150/ntno.58965