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Expert Opinion on Drug Discovery Aug 2019: Click chemistry has been exploited widely in the past to expedite lead discovery and optimization. Indeed, Copper-catalyzed azide-alkyne cycloaddition (CuAAC) click... (Review)
Review
: Click chemistry has been exploited widely in the past to expedite lead discovery and optimization. Indeed, Copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry is a bioorthogonal reaction of widespread utility throughout medicinal chemistry and chemical biology. : The authors review recent applications of CuAAC click chemistry to drug discovery based on the literature published since 2013. Furthermore, the authors provide the reader with their expert perspectives on the area including their outlook on future developments. : Click chemistry reactions are an important part of the medicinal chemistry toolbox and offer substantial advantages to medicinal chemists in terms of overcoming the limitations of useful chemical synthesis, increasing throughput, and improving the quality of compound libraries. To explore new chemical spaces for drug-like molecules containing a high degree of structural diversity, it may be useful to merge the diversity-oriented synthesis and 'privileged' substructure-based strategy with bioorthogonal reactions using sophisticated automation and flow systems to improve productivity. Large compound libraries obtained in this way should be of great value for the discovery of bioactive compounds and therapeutic agents.
Topics: Alkynes; Animals; Azides; Chemistry, Pharmaceutical; Click Chemistry; Copper; Cycloaddition Reaction; Drug Discovery; Humans
PubMed: 31094231
DOI: 10.1080/17460441.2019.1614910 -
Journal of the American Chemical Society Jun 2020Itaconate is an anti-inflammatory metabolite involved in pathogen-macrophage interactions, but the mechanisms underlying its effect are not fully understood. Competitive...
Itaconate is an anti-inflammatory metabolite involved in pathogen-macrophage interactions, but the mechanisms underlying its effect are not fully understood. Competitive cysteine profiling has been performed to interrogate itaconate's reactivity in cell lysates, but methods for analyzing targets of itaconation directly in living macrophages are still lacking. In this work, we developed a specific bioorthogonal probe, itaconate-alkyne (ITalk), for quantitative and site-specific chemoproteomic profiling of itaconation in inflammatory macrophages. ITalk recapitulates the anti-inflammatory property of itaconate and enables biochemical evaluation and proteomic analysis of its direct targets. Our study delineates the widespread landscape of itaconate substrates, providing a versatile tool and comprehensive resource for investigating its function.
Topics: A549 Cells; Alkynes; Animals; Anti-Inflammatory Agents; Cysteine; Glutathione; Humans; Macrophages; Mice; Molecular Probes; Proteins; Proteomics; RAW 264.7 Cells; Succinates
PubMed: 32496768
DOI: 10.1021/jacs.9b11962 -
Chemistry (Weinheim An Der Bergstrasse,... Aug 2022Heteroaryl boronic acids and esters are extremely important and valuable intermediates because of their wide application in the synthesis of marketed drugs and bioactive... (Review)
Review
Heteroaryl boronic acids and esters are extremely important and valuable intermediates because of their wide application in the synthesis of marketed drugs and bioactive compounds. Over the last couple of decades, the construction of highly important heteroaryl carbon-boron bonds has created huge attention. The transition-metal-free protocols are more green, less sensitive to air and moisture, and also economically advantageous over the transition-metal-based protocols. The transition-metal-free C-H borylation of heteroarenes and C-X (X=halogen) borylation of heteroaryl halides represents an excellent approach for their synthesis. Also, various cyclization and alkyne activation protocols have been recently established for their synthesis. The goal of this review article is to summarize the existing literature and the current state of the art for transition-metal-free synthesis of heteroaryl boronic acid and esters.
Topics: Alkynes; Boron; Boronic Acids; Carbon; Catalysis; Esters; Transition Elements
PubMed: 35438817
DOI: 10.1002/chem.202200556 -
Annual Review of Chemical and... Jun 2022Natural products are a diverse class of biologically produced compounds that participate in fundamental biological processes such as cell signaling, nutrient... (Review)
Review
Natural products are a diverse class of biologically produced compounds that participate in fundamental biological processes such as cell signaling, nutrient acquisition, and interference competition. Unique triple-bond functionalities like isonitriles and alkynes often drive bioactivity and may serve as indicators of novel chemical logic and enzymatic machinery. Yet, the biosynthetic underpinnings of these groups remain only partially understood, constraining the opportunity to rationally engineer biomolecules with these functionalities for applications in pharmaceuticals, bioorthogonal chemistry, and other value-added chemical processes. Here, we focus our review on characterized biosynthetic pathways for isonitrile and alkyne functionalities, their bioorthogonal transformations, and prospects for engineering their biosynthetic machinery for biotechnological applications.
Topics: Alkynes; Biological Products; Biosynthetic Pathways
PubMed: 35236086
DOI: 10.1146/annurev-chembioeng-092120-025140 -
Chemical Reviews Jun 2021At its basic conceptualization, photoclick chemistry embodies a collection of click reactions that are performed via the application of light. The emergence of this... (Review)
Review
At its basic conceptualization, photoclick chemistry embodies a collection of click reactions that are performed via the application of light. The emergence of this concept has had diverse impact over a broad range of chemical and biological research due to the spatiotemporal control, high selectivity, and excellent product yields afforded by the combination of light and click chemistry. While the reactions designated as "photoclick" have many important features in common, each has its own particular combination of advantages and shortcomings. A more extensive realization of the potential of this chemistry requires a broader understanding of the physical and chemical characteristics of the specific reactions. This review discusses the features of the most frequently employed photoclick reactions reported in the literature: photomediated azide-alkyne cycloadditions, other 1,3-dipolarcycloadditions, Diels-Alder and inverse electron demand Diels-Alder additions, radical alternating addition chain transfer additions, and nucleophilic additions. Applications of these reactions in a variety of chemical syntheses, materials chemistry, and biological contexts are surveyed, with particular attention paid to the respective strengths and limitations of each reaction and how that reaction benefits from its combination with light. Finally, challenges to broader employment of these reactions are discussed, along with strategies and opportunities to mitigate such obstacles.
Topics: Alkynes; Azides; Click Chemistry; Cycloaddition Reaction; Photochemistry
PubMed: 33835796
DOI: 10.1021/acs.chemrev.0c01212 -
Bioconjugate Chemistry Nov 2023The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists... (Review)
Review
The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based pretargeting.
Topics: Click Chemistry; Radiochemistry; Azides; Radiopharmaceuticals; Cycloaddition Reaction; Alkynes
PubMed: 37737084
DOI: 10.1021/acs.bioconjchem.3c00286 -
Methods in Molecular Biology (Clifton,... 2022Copper-catalyzed azide-alkyne cycloaddition (CuAAC) provides a simple and convenient strategy to synthesize diverse 1,2,3-triazoles for drug discovery. Described herein...
Copper-catalyzed azide-alkyne cycloaddition (CuAAC) provides a simple and convenient strategy to synthesize diverse 1,2,3-triazoles for drug discovery. Described herein is a protocol for the CuSO-catalyzed cycloaddition between alkynes and DNA-appended azides.
Topics: Alkynes; Azides; Catalysis; Click Chemistry; Copper; Cycloaddition Reaction; DNA; Triazoles
PubMed: 36083541
DOI: 10.1007/978-1-0716-2545-3_6 -
Angewandte Chemie (International Ed. in... Jul 2021A bioorthogonal reaction between N,N-dialkylhydroxylamines and push-pull-activated halogenated alkynes is described. We explore the use of rehybridization effects in...
A bioorthogonal reaction between N,N-dialkylhydroxylamines and push-pull-activated halogenated alkynes is described. We explore the use of rehybridization effects in activating alkynes, and we show that electronic effects, when competing stereoelectronic and inductive factors are properly balanced, sufficiently activate a linear alkyne in the uncatalyzed conjugative retro-Cope elimination reaction while adequately protecting it against cellular nucleophiles. This design preserves the low steric profile of an alkyne and pairs it with a comparably unobtrusive hydroxylamine. The kinetics are on par with those of the fastest strain-promoted azide-alkyne cycloaddition reactions, the products regioselectively formed, the components sufficiently stable and easily installed, and the reaction suitable for cellular labeling.
Topics: Alkynes; Amination; Azides; Cycloaddition Reaction; Molecular Structure
PubMed: 34019705
DOI: 10.1002/anie.202104863 -
Nature Communications Jun 2023The alkyne unit is a versatile building block in organic synthesis and the development of selective multifunctionalization of alkynes is an important object of research...
The alkyne unit is a versatile building block in organic synthesis and the development of selective multifunctionalization of alkynes is an important object of research in this field. Herein, we report an interesting gold-catalyzed, four-component reaction that achieves the oxo-arylfluorination or oxo-arylalkenylation of internal aromatic or aliphatic alkynes, efficiently breaking a carbon-carbon triple bond and forming four new chemical bonds. The reaction divergence can be controlled by site-directing functional groups in the alkynes; the presence of a phosphonate unit favors the oxo-arylfluorination, while the carboxylate motif benefits oxo-arylalkenylation. This reaction is enabled by an Au(I)/Au(III) redox coupling process using Selectfluor as both an oxidant and a fluorinating reagent. A wide range of structurally diverse α,α-disubstituted ketones, and tri- or tetra-substituted unsaturated ketones have been prepared in synthetically valuable yields and with excellent chemo-, regio- and stereoselectivity. The gram-scale preparation and late-stage application of complex alkynes have further enhanced their synthetic value.
Topics: Gold; Alkynes; Catalysis; Ketones; Carbon
PubMed: 37322071
DOI: 10.1038/s41467-023-39243-5 -
Organic & Biomolecular Chemistry Sep 2022The hydroarylation of alkynes, alkenes, and allenes is a cost-effective and efficient way to incorporate unsaturated moieties into aromatic substrates. This review... (Review)
Review
The hydroarylation of alkynes, alkenes, and allenes is a cost-effective and efficient way to incorporate unsaturated moieties into aromatic substrates. This review focuses on gold-catalyzed hydroarylation, which produces aromatic alkenes, diaryl-alkanes, heterocycles, carbocycles, and arylbutadienes by directly functionalizing C-H bonds. Without the need for prefunctionalization, direct functionalization of aromatic C-H bonds with unsaturated moieties (alkyne, alkene, allene) provides an efficient synthetic strategy with fewer reaction steps. This review offers an overview of the recently developed hydroarylation processes catalyzed by gold. Mechanisms of hydroarylation alkyne, alkene, allene, and arene activation receive special attention.
Topics: Alkadienes; Alkanes; Alkenes; Alkynes; Catalysis; Gold
PubMed: 36069264
DOI: 10.1039/d2ob00960a