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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 -
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 -
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 -
Chemical Communications (Cambridge,... Apr 2022C-H Azidation is an increasingly important tool for bioconjugation, materials chemistry, and the synthesis of nitrogen-containing natural products. While several...
C-H Azidation is an increasingly important tool for bioconjugation, materials chemistry, and the synthesis of nitrogen-containing natural products. While several approaches have been developed, these often require exotic and energetic reagents, expensive photocatalysts, or both. Here we report a simple and general C-H azidation reaction using earth-abundant tetra--butylammonium decatungstate as a photocatalyst and commercial -acetamidobenzenesulfonyl azide (-ABSA) as the azide source. This system can azidate a variety of unactivated C(sp)-H bonds in moderate to good yields and excellent turnover numbers. Preliminary mechanistic experiments implicate a radical mechanism proceeding photo-hydrogen atom transfer (photo-HAT).
Topics: Azides; Catalysis; Hydrogen; Nitrogen
PubMed: 35348566
DOI: 10.1039/d2cc00425a -
Nature Chemistry Dec 2020Metabolic glycoengineering with unnatural sugars provides a powerful tool to label cell membranes with chemical tags for subsequent targeted conjugation of molecular... (Review)
Review
Metabolic glycoengineering with unnatural sugars provides a powerful tool to label cell membranes with chemical tags for subsequent targeted conjugation of molecular cargos via efficient chemistries. This technology has been widely explored for cancer labelling and targeting. However, as this metabolic labelling process can occur in both cancerous and normal cells, cancer-selective labelling needs to be achieved to develop cancer-targeted therapies. Unnatural sugars can be either rationally designed to enable preferential labelling of cancer cells, or specifically delivered to cancerous tissues. In this Review Article, we will discuss the progress to date in design and delivery of unnatural sugars for metabolic labelling of tumour cells and subsequent development of tumour-targeted therapy. Metabolic cell labelling for cancer immunotherapy will also be discussed. Finally, we will provide a perspective on future directions of metabolic labelling of cancer and immune cells for the development of potent, clinically translatable cancer therapies.
Topics: Animals; Antineoplastic Agents; Azides; Cell Line, Tumor; Cell Membrane; Click Chemistry; Drug Carriers; Humans; Immunotherapy; Monosaccharides; Neoplasms; Polysaccharides
PubMed: 33219365
DOI: 10.1038/s41557-020-00587-w -
Nature Chemistry Aug 2021Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept...
Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with 'real time' drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy.
Topics: Animals; Antineoplastic Agents; Azides; Doxorubicin; Female; Fluorescent Dyes; Gamma Rays; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Indazoles; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oxidation-Reduction; Prodrugs; Proof of Concept Study; Pyrimidines; Sulfonamides; X-Rays; Xenograft Model Antitumor Assays; Mice
PubMed: 34112990
DOI: 10.1038/s41557-021-00711-4 -
Molecules (Basel, Switzerland) May 2024Azido-modified nucleosides have been extensively explored as substrates for click chemistry and the metabolic labeling of DNA and RNA. These compounds are also of... (Review)
Review
Azido-modified nucleosides have been extensively explored as substrates for click chemistry and the metabolic labeling of DNA and RNA. These compounds are also of interest as precursors for further synthetic elaboration and as therapeutic agents. This review discusses the chemistry of azidonucleosides related to the generation of nitrogen-centered radicals (NCRs) from the azido groups that are selectively inserted into the nucleoside frame along with the subsequent chemistry and biological implications of NCRs. For instance, the critical role of the sulfinylimine radical generated during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxy pyrimidine nucleotides as well as the NCRs generated from azidonucleosides by radiation-produced (prehydrated and aqueous) electrons are discussed. Regio and stereoselectivity of incorporation of an azido group ("radical arm") into the frame of nucleoside and selective generation of NCRs under reductive conditions, which often produce the same radical species that are observed upon ionization events due to radiation and/or other oxidative conditions that are emphasized. NCRs generated from nucleoside-modified precursors other than azidonucleosides are also discussed but only with the direct relation to the same/similar NCRs derived from azidonucleosides.
Topics: Nucleosides; Azides; Nitrogen; Free Radicals; Click Chemistry
PubMed: 38792171
DOI: 10.3390/molecules29102310 -
Chemical Reviews Jun 2021Click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on... (Review)
Review
Click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on multiple scientific disciplines, and its implementation within the nucleic acid field has enabled researchers to generate a wide variety of tools with application in biology, biochemistry, and biotechnology. Azide-alkyne cycloadditions (AAC) are still the leading technology among click reactions due to the facile modification and incorporation of azide and alkyne groups within biological scaffolds. Application of AAC chemistry to nucleic acids allows labeling, ligation, and cyclization of oligonucleotides efficiently and cost-effectively relative to previously used chemical and enzymatic techniques. In this review, we provide a guide to inexperienced and knowledgeable researchers approaching the field of click chemistry with nucleic acids. We discuss in detail the chemistry, the available modified-nucleosides, and applications of AAC reactions in nucleic acid chemistry and provide a critical view of the advantages, limitations, and open-questions within the field.
Topics: Alkynes; Azides; Click Chemistry; Cycloaddition Reaction; Nucleic Acids; Thermodynamics
PubMed: 33443411
DOI: 10.1021/acs.chemrev.0c00928 -
Molecules (Basel, Switzerland) Jun 2021Although a plethora of chemistries have been developed to selectively decorate protein molecules, novel strategies continue to be reported with the final aim of... (Review)
Review
Although a plethora of chemistries have been developed to selectively decorate protein molecules, novel strategies continue to be reported with the final aim of improving selectivity and mildness of the reaction conditions, preserve protein integrity, and fulfill all the increasing requirements of the modern applications of protein conjugates. The targeting of the protein N-terminal alpha-amine group appears a convenient solution to the issue, emerging as a useful and unique reactive site universally present in each protein molecule. Herein, we provide an updated overview of the methodologies developed until today to afford the selective modification of proteins through the targeting of the N-terminal alpha-amine. Chemical and enzymatic strategies enabling the selective labeling of the protein N-terminal alpha-amine group are described.
Topics: Amines; Azides; Binding Sites; Click Chemistry; Molecular Probe Techniques; Protein Domains; Proteins
PubMed: 34207845
DOI: 10.3390/molecules26123521 -
Methods in Molecular Biology (Clifton,... 2023Click chemistry, and particularly azide-alkyne cycloaddition, represents one of the principal bioconjugation strategies that can be used to conveniently attach various...
Click chemistry, and particularly azide-alkyne cycloaddition, represents one of the principal bioconjugation strategies that can be used to conveniently attach various ligands to the surface of preformed liposomes. This efficient and chemoselective reaction involves a Cu(I)-catalyzed azide-alkyne cycloaddition which can be performed under mild experimental conditions in aqueous media. Here we describe the application of a model click reaction to the conjugation, in a single step, of unprotected α-1-thiomannosyl ligands, functionalized with an azide group, to liposomes containing a terminal alkyne-functionalized lipid anchor. Excellent coupling yields were obtained in the presence of bathophenanthrolinedisulphonate, a water-soluble copper-ion chelator, acting as catalyst. No vesicle leakage was triggered by this conjugation reaction, and the coupled mannose ligands were exposed at the surface of the liposomes. The major limitation of Cu(I)-catalyzed click reactions is that this type of conjugation is restricted to liposomes made of saturated (phospho)lipids. To circumvent this constraint, an example of alternate copper-free azide-alkyne click reaction has been developed, and it was applied to the anchoring of a biotin moiety that was fully functional and could be therefore quantified. Molecular tools and results are presented here.
Topics: Liposomes; Click Chemistry; Azides; Catalysis; Alkynes; Ligands; Cycloaddition Reaction
PubMed: 36781760
DOI: 10.1007/978-1-0716-2954-3_15