Chemistry › Organic Chemistry

Click Chemistry and Applications

Works Count: 41361

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Description

This cluster of papers focuses on the application of click chemistry, particularly the copper-catalyzed azide-alkyne cycloaddition, in chemical biology and drug development. It explores diverse chemical functionality, bioorthogonal chemistry, protein labeling, in vivo imaging, triazole synthesis, and the development of enzyme inhibitors.

Keywords

Click Chemistry; Copper-Catalyzed Cycloaddition; Bioorthogonal Chemistry; Azides and Alkynes; Chemical Functionality; Drug Discovery; Protein Labeling; In Vivo Imaging; Triazole Synthesis; Enzyme Inhibitors

A Strain-Promoted [3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems

2004-11-01

Nicholas J. Agard , Jennifer A. Prescher , Carolyn R. Bertozzi

Selective chemical reactions that are orthogonal to the diverse functionality of biological systems have become important tools in the field of chemical biology. Two notable examples are the Staudinger ligation … Selective chemical reactions that are orthogonal to the diverse functionality of biological systems have become important tools in the field of chemical biology. Two notable examples are the Staudinger ligation of azides and phosphines and the Cu(I)-catalyzed [3 + 2] cycloaddition of azides and alkynes ("click chemistry"). The Staudinger ligation has sufficient biocompatibility for performance in living animals but suffers from phosphine oxidation and synthetic challenges. Click chemistry obviates the requirement of phosphines, but the Cu(I) catalyst is toxic to cells, thereby precluding in vivo applications. Here we present a strain-promoted [3 + 2] cycloaddition between cyclooctynes and azides that proceeds under physiological conditions without the need for a catalyst. The utility of the reaction was demonstrated by selective modification of biomolecules in vitro and on living cells, with no apparent toxicity.

Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides

2002-04-02

Christian W. Tornøe , Caspar Christensen , Morten Meldal

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase … The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

2005-08-15

Stefan Bräse , Carmen Gil , Kerstin Knepper +1 more

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely … Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aubé rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

2011-08-29

Sandip G. Agalave , Suleman R. Maujan , Vandana S. Pore

Abstract The copper(I)‐catalyzed 1,2,3‐triazole‐forming reaction between azides and terminal alkynes has become the gold standard of ‘click chemistry’ due to its reliability, specificity, and biocompatibility. Applications of click chemistry are … Abstract The copper(I)‐catalyzed 1,2,3‐triazole‐forming reaction between azides and terminal alkynes has become the gold standard of ‘click chemistry’ due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target‐templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen‐bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3‐triazole moiety as pharmacophore.

Cell Surface Engineering by a Modified Staudinger Reaction

2000-03-17

Eliana Saxon , Carolyn R. Bertozzi

Selective chemical reactions enacted within a cellular environment can be powerful tools for elucidating biological processes or engineering novel interactions. A chemical transformation that permits the selective formation of covalent … Selective chemical reactions enacted within a cellular environment can be powerful tools for elucidating biological processes or engineering novel interactions. A chemical transformation that permits the selective formation of covalent adducts among richly functionalized biopolymers within a cellular context is presented. A ligation modeled after the Staudinger reaction forms an amide bond by coupling of an azide and a specifically engineered triarylphosphine. Both reactive partners are abiotic and chemically orthogonal to native cellular components. Azides installed within cell surface glycoconjugates by metabolism of a synthetic azidosugar were reacted with a biotinylated triarylphosphine to produce stable cell-surface adducts. The tremendous selectivity of the transformation should permit its execution within a cell's interior, offering new possibilities for probing intracellular interactions.

Thiol-ene “click” reactions and recent applications in polymer and materials synthesis

2009-11-25

Andrew B. Lowe

This review highlights examples of recent applications of both the radical-mediated and base/nucleophile-initiated thiol-ene reactions in polymer and materials synthesis. Initial discussion focuses on mechanistic aspects of these reactions and … This review highlights examples of recent applications of both the radical-mediated and base/nucleophile-initiated thiol-ene reactions in polymer and materials synthesis. Initial discussion focuses on mechanistic aspects of these reactions and also notes some of the structural considerations, with respect to reactants, that should be considered when practising such chemistries. The review is not intended to be exhaustive but rather to serve as an illustration of the impressive versatility and clear potential of these thiol-based "click" reactions and to highlight examples demonstrating its broad utility.

Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates

2004-12-08

Fahmi Himo , Timothy Lovell , Robert Hilgraf +4 more

Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and … Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.

Copper-free click chemistry for dynamic in vivo imaging

2007-10-18

Jeremy M. Baskin , Jennifer A. Prescher , Scott T. Laughlin +6 more

Dynamic imaging of proteins in live cells is routinely performed by using genetically encoded reporters, an approach that cannot be extended to other classes of biomolecules such as glycans and … Dynamic imaging of proteins in live cells is routinely performed by using genetically encoded reporters, an approach that cannot be extended to other classes of biomolecules such as glycans and lipids. Here, we report a Cu-free variant of click chemistry that can label these biomolecules rapidly and selectively in living systems, overcoming the intrinsic toxicity of the canonical Cu-catalyzed reaction. The critical reagent, a substituted cyclooctyne, possesses ring strain and electron-withdrawing fluorine substituents that together promote the [3 + 2] dipolar cycloaddition with azides installed metabolically into biomolecules. This Cu-free click reaction possesses comparable kinetics to the Cu-catalyzed reaction and proceeds within minutes on live cells with no apparent toxicity. With this technique, we studied the dynamics of glycan trafficking and identified a population of sialoglycoconjugates with unexpectedly rapid internalization kinetics.

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Cu-free click cycloaddition reactions in chemical biology

2010-01-01

John C. Jewett , Carolyn R. Bertozzi

Bioorthogonal chemical reactions are paving the way for new innovations in biology. These reactions possess extreme selectivity and biocompatibility, such that their participating reagents can form covalent bonds within richly … Bioorthogonal chemical reactions are paving the way for new innovations in biology. These reactions possess extreme selectivity and biocompatibility, such that their participating reagents can form covalent bonds within richly functionalized biological systems—in some cases, living organisms. This tutorial review will summarize the history of this emerging field, as well as recent progress in the development and application of bioorthogonal copper-free click cycloaddition reactions.

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The resurgence of covalent drugs

2011-04-01

Juswinder Singh , Russell C. Petter , Thomas A. Baillie +1 more

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Thiol-click chemistry: a multifaceted toolbox for small molecule and polymer synthesis

2010-01-01

Charles E. Hoyle , Andrew B. Lowe , Christopher N. Bowman

The merits of thiol-click chemistry and its potential for making new forays into chemical synthesis and materials applications are described. Since thiols react to high yields under benign conditions with … The merits of thiol-click chemistry and its potential for making new forays into chemical synthesis and materials applications are described. Since thiols react to high yields under benign conditions with a vast range of chemical species, their utility extends to a large number of applications in the chemical, biological, physical, materials and engineering fields. This critical review provides insight into emerging venues for application as well as new mechanistic understanding of this exceptional chemistry in its many forms (81 references).

Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3 + 2] Cycloaddition

2003-02-22

Qian Wang , Timothy R. Chan , Robert Hilgraf +3 more

The copper-catalyzed cycloaddition reaction between azides and alkynes functions efficiently in aqueous solution in the presence of a tris(triazolyl)amine ligand. The process has been employed to make rapid and reliable … The copper-catalyzed cycloaddition reaction between azides and alkynes functions efficiently in aqueous solution in the presence of a tris(triazolyl)amine ligand. The process has been employed to make rapid and reliable covalent connections to micromolar concentrations of protein decorated with either of the reactive moieties. The chelating ligand plays a crucial role in stabilizing the Cu(I) oxidation state and protecting the protein from Cu(triazole)-induced denaturation. Because the azide and alkyne groups themselves are unreactive with protein residues or other biomolecules, their ligation is of potential utility as a general bioconjugation method.

The Thiol-Michael Addition Click Reaction: A Powerful and Widely Used Tool in Materials Chemistry

2013-08-19

Devatha P. Nair , Maciej Podgórski , Shunsuke Chatani +4 more

The key attribute of the thiol-Michael addition reaction that makes it a prized tool in materials science is its modular "click" nature, which allows for the implementation of this highly … The key attribute of the thiol-Michael addition reaction that makes it a prized tool in materials science is its modular "click" nature, which allows for the implementation of this highly efficient, "green" reaction in applications that vary from small molecule synthesis to in situ polymer modifications in biological systems to the surface functionalization of material coatings. Over the past few decades, interest in the thiol-Michael addition reaction has increased dramatically, as is evidenced by the number of studies that have been dedicated to elucidating different aspects of the reaction that range from an in-depth analysis aimed at understanding the mechanistic pathways of the reaction to synthetic studies that have examined modifying molecular structures with the aim of yielding highly efficient thiol-Michael reaction monomers. This review examines the reaction mechanisms, the substrates and catalysts used in the reaction, and the subsequent implementation of the thiol-Michael reaction in materials science over the years, with particular emphasis on the recent developments in the arena over the past decade.

Cu-Catalyzed Azide−Alkyne Cycloaddition

2008-08-01

Morten Meldal , Christian W. Tornøe

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCu-Catalyzed Azide−Alkyne CycloadditionMorten Meldal*† and Christian Wenzel Tornøe‡View Author Information Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark, and H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCu-Catalyzed Azide−Alkyne CycloadditionMorten Meldal*† and Christian Wenzel Tornøe‡View Author Information Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark, and H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark* Corresponding author: telephone, +45 3327 4708; fax, +45 3327 501; e-mail, [email protected]†Carlsberg Laboratory.‡H. Lundbeck A/S. E-mail: [email protected].Cite this: Chem. Rev. 2008, 108, 8, 2952–3015Publication Date (Web):August 13, 2008Publication History Received30 November 2007Published online13 August 2008Published inissue 1 August 2008https://pubs.acs.org/doi/10.1021/cr0783479https://doi.org/10.1021/cr0783479review-articleACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views67045Altmetric-Citations3956LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Azides,Hydrocarbons,Peptides and proteins,Polymers,Triazole Get e-Alerts

Activity-based protein profiling: The serine hydrolases

1999-12-21

Yongsheng Liu , Matthew P. Patricelli , Benjamin F. Cravatt

With the postgenome era rapidly approaching, new strategies for the functional analysis of proteins are needed. To date, proteomics efforts have primarily been confined to recording variations in protein level … With the postgenome era rapidly approaching, new strategies for the functional analysis of proteins are needed. To date, proteomics efforts have primarily been confined to recording variations in protein level rather than activity. The ability to profile classes of proteins on the basis of changes in their activity would greatly accelerate both the assignment of protein function and the identification of potential pharmaceutical targets. Here, we describe the chemical synthesis and utility of an active-site directed probe for visualizing dynamics in the expression and function of an entire enzyme family, the serine hydrolases. By reacting this probe, a biotinylated fluorophosphonate referred to as FP-biotin, with crude tissue extracts, we quickly and with high sensitivity detect numerous serine hydrolases, many of which display tissue-restricted patterns of expression. Additionally, we show that FP-biotin labels these proteins in an activity-dependent manner that can be followed kinetically, offering a powerful means to monitor dynamics simultaneously in both protein function and expression.

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An amplified sensitivity arising from covalent modification in biological systems.

1981-11-01

Albert Goldbeter , Daniel E. Koshland

The transient and steady-state behavior of a reversible covalent modification system is examined. When the modifying enzymes operate outside the region of first-order kinetics, small percentage changes in the concentration … The transient and steady-state behavior of a reversible covalent modification system is examined. When the modifying enzymes operate outside the region of first-order kinetics, small percentage changes in the concentration of the effector controlling either of the modifying enzymes can give much larger percentage changes in the amount of modified protein. This amplification of the response to a stimulus can provide additional sensitivity in biological control, equivalent to that of allosteric proteins with high Hill coefficients.

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Click Chemistry: Diverse Chemical Function from a Few Good Reactions

2001-06-01

Hartmuth C. Kolb , M. G. Finn , K. Barry Sharpless

Examination of nature's favorite molecules reveals a striking preference for making carbon–heteroatom bonds over carbon–carbon bonds—surely no surprise given that carbon dioxide is nature's starting material and that most reactions … Examination of nature's favorite molecules reveals a striking preference for making carbon–heteroatom bonds over carbon–carbon bonds—surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon–heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C−C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C−X−C), an approach we call “click chemistry”. Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect “spring-loaded” reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

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Tetrazine Ligation: Fast Bioconjugation Based on Inverse-Electron-Demand Diels−Alder Reactivity

2008-09-18

Melissa L. Blackman , Maksim Royzen , Joseph M. Fox

Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of … Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. The rate of the ligation between trans-cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine is very rapid (k2 2000 M−1 s−1). This fast reactivity enables protein modification at low concentration.

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Large rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implications

1991-12-01

Vittorio Farina , Bala Krishnan

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLarge rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implicationsVittorio Farina and Bala KrishnanCite this: J. Am. Chem. Soc. … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLarge rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implicationsVittorio Farina and Bala KrishnanCite this: J. Am. Chem. Soc. 1991, 113, 25, 9585–9595Publication Date (Print):December 1, 1991Publication History Published online1 May 2002Published inissue 1 December 1991https://pubs.acs.org/doi/10.1021/ja00025a025https://doi.org/10.1021/ja00025a025research-articleACS PublicationsRequest reuse permissionsArticle Views7993Altmetric-Citations957LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Discovery and Development of Folic-Acid-Based Receptor Targeting for Imaging and Therapy of Cancer and Inflammatory Diseases

2007-07-27

Philip S. Low , Walter A. Henne , Derek D. Doorneweerd

In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that … In order to avoid the toxicities associated with prescription drug use today, we have explored novel methods for delivering drugs selectively to pathologic cells, thereby avoiding the collateral damage that accompanies their uptake by healthy cells. In this Account, we describe our quest for the ideal targeted therapeutic agent. This effort began with a search for ligands that would bind selectively to pathologic cells, displaying no affinity for healthy cells. After identification of an optimal targeting ligand, effort was focused on construction of linkers that would carry the attached drug to pathologic cells with receptors for the selected ligand. In the case of cancer, we exploited the well-characterized up-regulation of folate receptors on malignant cells to target folate-linked pharmaceuticals to cancer tissues in vivo. Drugs that have been linked to folic acid for tumor-selective drug delivery to date include (i) protein toxins, (ii) chemotherapeutic agents, (iii) gene therapy vectors, (iv) oligonucleotides (including small interfering RNA (siRNA)), (v) radioimaging agents, (vi) magnetic resonance imaging (MRI) contrast agents, (vii) liposomes with entrapped drugs, (viii) radiotherapeutic agents, (ix) immunotherapeutic agents, and (x) enzyme constructs for prodrug therapy. Current clinical trials of four folate-linked drugs demonstrate that folate receptor-targeting holds great promise for increasing the potency while reducing toxicity of many cancer therapies. In the course of developing folate-conjugated drugs for cancer, we discovered that folate receptors are also overexpressed on activated (but not resting or quiescent) macrophages. Recognizing that activated macrophages either cause or contribute to such diseases as rheumatoid arthritis, Crohn's disease, atherosclerosis, lupus, inflammatory osteoarthritis, diabetes, ischemia reperfusion injury, glomerulonephritis, sarcoidosis, psoriasis, Sjogren's disease, and vasculitis, we initiated studies aimed at developing folate-conjugated imaging and therapeutic agents for the diagnosis and treatment of such diseases. In very brief time, significant progress has been made towards identification of clinical candidates for targeted treatment of several inflammatory and autoimmune diseases. This Account summarizes the discovery and development of a variety of folate-targeted drugs for the diagnosis and therapy of cancers and inflammatory/autoimmune diseases.

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(i) acetylides

2010-01-01

Jason E. Hein , Valery V. Fokin

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, … Copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(I) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science.

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Click Chemistry for Drug Development and Diverse Chemical–Biology Applications

2013-03-27

Thirumurugan Prakasam , Dariusz Matosiuk , Krzysztof Jóźwiak

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTClick Chemistry for Drug Development and Diverse Chemical–Biology ApplicationsPrakasam Thirumurugan†, Dariusz Matosiuk‡, and Krzysztof Jozwiak*†View Author Information† †Laboratory of Medical Chemistry and Neuroengineering, Department of Chemistry, and … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTClick Chemistry for Drug Development and Diverse Chemical–Biology ApplicationsPrakasam Thirumurugan†, Dariusz Matosiuk‡, and Krzysztof Jozwiak*†View Author Information† †Laboratory of Medical Chemistry and Neuroengineering, Department of Chemistry, and ‡Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Lublin 20093, Poland*E-mail: [email protected]Cite this: Chem. Rev. 2013, 113, 7, 4905–4979Publication Date (Web):March 27, 2013Publication History Received25 October 2011Published online27 March 2013Published inissue 10 July 2013https://pubs.acs.org/doi/10.1021/cr200409fhttps://doi.org/10.1021/cr200409freview-articleACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views40218Altmetric-Citations1527LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical synthesis,Inhibitors,Monomers,Peptides and proteins,Receptors Get e-Alerts

Chemistry in living systems

2005-05-25

Jennifer A. Prescher , Carolyn R. Bertozzi

‘Click’ Chemistry in Polymer and Materials Science

2007-01-05

Wolfgang H. Binder , Robert Sachsenhofer

Abstract The modification of polymers after the successful achievement of a polymerization process represents an important task in macromolecular science. Cycloaddition reactions, among them the metal catalyzed azide/alkyne ‘click’ reaction … Abstract The modification of polymers after the successful achievement of a polymerization process represents an important task in macromolecular science. Cycloaddition reactions, among them the metal catalyzed azide/alkyne ‘click’ reaction (a variation of the Huisgen 1,3‐dipolar cycloaddition reaction between terminal acetylenes and azides) represents an important contribution towards this endeavor. They combine high efficiency (usually above 95%) with a high tolerance of functional groups and solvents, as well as moderate reaction temperatures (25–70 °C). The present review assembles recent literature for applications of this reaction in the field of polymer science (linear polymers, dendrimers, gels) as well as the use of this and related reactions for surface modification on carbon nanotubes, fullerenes, and on solid substrates, and includes the authors own publications in this field. A number of references (>100) are included. magnified image

Polytriazoles as Copper(I)-Stabilizing Ligands in Catalysis

2004-07-30

Timothy R. Chan , Robert Hilgraf , K. Barry Sharpless +1 more

Polytriazolylamines were synthesized by the copper(I)-catalyzed ligation of azides and alkynes. The C3-symmetric derivative, TBTA, was shown to be a powerful stabilizing ligand for copper(I), protecting it from oxidation and … Polytriazolylamines were synthesized by the copper(I)-catalyzed ligation of azides and alkynes. The C3-symmetric derivative, TBTA, was shown to be a powerful stabilizing ligand for copper(I), protecting it from oxidation and disproportionation, while enhancing its catalytic activity.

A chemical method for fast and sensitive detection of DNA synthesis in vivo

2008-02-13

Adrian Salic , Timothy J. Mitchison

We have developed a method to detect DNA synthesis in proliferating cells, based on the incorporation of 5-ethynyl-2′-deoxyuridine (EdU) and its subsequent detection by a fluorescent azide through a Cu(I)-catalyzed … We have developed a method to detect DNA synthesis in proliferating cells, based on the incorporation of 5-ethynyl-2′-deoxyuridine (EdU) and its subsequent detection by a fluorescent azide through a Cu(I)-catalyzed [3 + 2] cycloaddition reaction (“click” chemistry). Detection of the EdU label is highly sensitive and can be accomplished in minutes. The small size of the fluorescent azides used for detection results in a high degree of specimen penetration, allowing the staining of whole-mount preparations of large tissue and organ explants. In contrast to BrdU, the method does not require sample fixation or DNA denaturation and permits good structural preservation. We demonstrate the use of the method in cultured cells and in the intestine and brain of whole animals.

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Specific Covalent Labeling of Recombinant Protein Molecules Inside Live Cells

1998-07-10

B. Albert Griffin , Stephen Adams , Roger Y. Tsien

Recombinant proteins containing four cysteines at the i , i + 1, i + 4, and i + 5 positions of an α helix were fluorescently labeled in living cells … Recombinant proteins containing four cysteines at the i , i + 1, i + 4, and i + 5 positions of an α helix were fluorescently labeled in living cells by extracellular administration of 4′,5′-bis(1,3,2-dithioarsolan-2-yl)fluorescein. This designed small ligand is membrane-permeant and nonfluorescent until it binds with high affinity and specificity to the tetracysteine domain. Such in situ labeling adds much less mass than does green fluorescent protein and offers greater versatility in attachment sites as well as potential spectroscopic and chemical properties. This system provides a recipe for slightly modifying a target protein so that it can be singled out from the many other proteins inside live cells and fluorescently stained by small nonfluorescent dye molecules added from outside the cells.

The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures

2003-02-22

Douglas A. Horton , Gregory T. Bourne , Mark L. Smythe

ADVERTISEMENT RETURN TO ISSUEPREVArticleThe Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged SubstructuresDouglas A. Horton, Gregory T. Bourne, and Mark L. SmytheView Author Information Institute for Molecular Bioscience, The University … ADVERTISEMENT RETURN TO ISSUEPREVArticleThe Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged SubstructuresDouglas A. Horton, Gregory T. Bourne, and Mark L. SmytheView Author Information Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072, Qld., Australia, and Protagonist Pty. Ltd., Level 7 Gehrmann Laboratories, The University of Queensland, St. Lucia, 4072, Qld., Australia Cite this: Chem. Rev. 2003, 103, 3, 893–930Publication Date (Web):February 22, 2003Publication History Received1 October 2002Published online22 February 2003Published inissue 1 March 2003https://pubs.acs.org/doi/10.1021/cr020033shttps://doi.org/10.1021/cr020033sresearch-articleACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views18783Altmetric-Citations2696LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aromatic compounds,Combinatorial synthesis,Molecules,Receptors,Scaffolds Get e-Alerts

Chemistry and Biology Of Multicomponent Reactions

2012-03-22

Alexander Dömlingꝉ , Wei Wang , Kan Wang

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTChemistry and Biology Of Multicomponent ReactionsAlexander Dömling*†‡, Wei Wang†§, and Kan Wang†View Author Information† Department of Pharmaceutical Sciences, University of Pittsburgh, Biomedical Science Tower 3, Suite 10019, … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTChemistry and Biology Of Multicomponent ReactionsAlexander Dömling*†‡, Wei Wang†§, and Kan Wang†View Author Information† Department of Pharmaceutical Sciences, University of Pittsburgh, Biomedical Science Tower 3, Suite 10019, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, United States‡ Chair of Drug Design, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands§ Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, P. R. China*E-mail: [email protected]. Fax: (+)412-383-5298.Cite this: Chem. Rev. 2012, 112, 6, 3083–3135Publication Date (Web):March 22, 2012Publication History Received23 July 2010Published online22 March 2012Published inissue 13 June 2012https://pubs.acs.org/doi/10.1021/cr100233rhttps://doi.org/10.1021/cr100233rreview-articleACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views31588Altmetric-Citations1987LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Inhibitors,Peptides and proteins,Reaction products,Receptors,Scaffolds Get e-Alerts

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Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

2014-08-11

Jiajia Dong , Larissa B. Krasnova , M. G. Finn +1 more

Abstract Aryl sulfonyl chlorides (e.g. Ts‐Cl) are beloved of organic chemists as the most commonly used S VI electrophiles, and the parent sulfuryl chloride, O 2 S VI Cl 2 … Abstract Aryl sulfonyl chlorides (e.g. Ts‐Cl) are beloved of organic chemists as the most commonly used S VI electrophiles, and the parent sulfuryl chloride, O 2 S VI Cl 2 , has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S VI Cl bond is exceedingly sensitive to reductive collapse yielding S IV species and Cl − . Fortunately, the use of sulfur(VI) fluorides (e.g., R‐SO 2 ‐F and SO 2 F 2 ) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany. 6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid‐20th century. Here we seek to revive it, along with John Hyatt’s unnoticed 1979 full paper exposition on CH 2 CH‐SO 2 ‐F, the most perfect Michael acceptor ever found. 98 To this history we add several new observations, including that the otherwise very stable gas SO 2 F 2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.

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Organic chemistry in water

2005-11-21

Chao‐Jun Li , Liang Chen

Water has emerged as a versatile solvent for organic chemistry in recent years. Water as a solvent is not only inexpensive and environmentally benign, but also gives completely new reactivity. … Water has emerged as a versatile solvent for organic chemistry in recent years. Water as a solvent is not only inexpensive and environmentally benign, but also gives completely new reactivity. The types of organic reactions in water are broad including pericyclic reactions, reactions of carbanion equivalent, reactions of carbocation equivalent, reactions of radicals and carbenes, transition-metal catalysis, oxidations-reductions, which we discuss in this tutorial review. Aqueous organic reactions have broad applications such as synthesis of biological compounds from carbohydrates and chemical modification of biomolecules.

Click-Chemie: diverse chemische Funktionalität mit einer Handvoll guter Reaktionen

2001-06-01

Hartmuth C. Kolb , M. G. Finn , K. Barry Sharpless

Betrachtet man die in der Natur am häufigsten vorkommenden Verbindungen, so fällt auf, dass die Bildung von Kohlenstoff-Heteroatom-Bindungen gegenüber der von Kohlenstoff-Kohlenstoff-Bindungen deutlich bevorzugt ist. Da zum einen Kohlendioxid die … Betrachtet man die in der Natur am häufigsten vorkommenden Verbindungen, so fällt auf, dass die Bildung von Kohlenstoff-Heteroatom-Bindungen gegenüber der von Kohlenstoff-Kohlenstoff-Bindungen deutlich bevorzugt ist. Da zum einen Kohlendioxid die Basisverbindung der Natur ist und andererseits das Medium natürlicher Reaktionen zumeist Wasser ist, überrascht dies sicherlich nicht. Nucleinsäuren, Proteine und Polysaccharide sind polymere Kondensationsprodukte kleiner Untereinheiten, die durch Kohlenstoff-Heteroatom-Bindungen verknüpft sind. Sogar die etwa 35 Baueinheiten, aus denen diese essentiellen Verbindungen bestehen, enthalten nicht mehr als sechs aufeinander folgende C-C-Bindungen, sieht man einmal von den drei aromatischen Aminosäuren ab. Mit der Natur als Vorbild richteten wir unser Interesse auf die Entwicklung leistungsfähiger, gut funktionierender und selektiver Reaktionen für die effiziente Synthese neuartiger nützlicher Verbindungen sowie kombinatorischer Bibliotheken mittels Heteroatomverknüpfungen (C-X-C). Diese Synthesestrategie nennen wir „Click-Chemie“. Click-Chemie ist durch eine Auswahl einiger weniger nahezu idealer Reaktionen charakterisiert, mit all ihren Grenzen und Möglichkeiten. In diesem Beitrag werden zum einen die strengen Kriterien, die Reaktionen erfüllen müssen, um die Bezeichnung „Click-Chemie“ zu verdienen, definiert, zum anderen werden Beispiele für molekulare Strukturen gegeben, die mit dieser spartanischen, aber dennoch leistungsfähigen Synthesestrategie leicht hergestellt werden können.

The growing applications of click chemistry

2007-01-01

John E. Moses , Adam D. Moorhouse

Click chemistry, the subject of this tutorial review, is a modular synthetic approach towards the assembly of new molecular entities. This powerful strategy relies mainly upon the construction of carbon-heteroatom … Click chemistry, the subject of this tutorial review, is a modular synthetic approach towards the assembly of new molecular entities. This powerful strategy relies mainly upon the construction of carbon-heteroatom bonds using spring-loaded reactants. Its growing number of applications are found in nearly all areas of modern chemistry from drug discovery to materials science. The copper(I)-catalysed 1,2,3-triazole forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to its reliability, specificity and biocompatibility.

A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes

2002-07-15

Vsevolod V. Rostovtsev , Luke G. Green , Valery V. Fokin +1 more

By simply stirring in water, organic azides and terminal alkynes are readily and cleanly converted into 1,4-disubstituted 1,2,3-triazoles through a highly efficient and regioselective copper(I)-catalyzed process (see scheme for an … By simply stirring in water, organic azides and terminal alkynes are readily and cleanly converted into 1,4-disubstituted 1,2,3-triazoles through a highly efficient and regioselective copper(I)-catalyzed process (see scheme for an example). Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2002/z19191_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

CuI‐Catalyzed Alkyne–Azide “Click” Cycloadditions from a Mechanistic and Synthetic Perspective

2005-10-25

Victoria D. Bock , Henk Hiemstra , Jan H. van Maarseveen

Abstract Cu I ‐catalyzed alkyne–azide cycloaddition provides 1,4‐disubstituted 1,2,3‐triazoles with such efficiency and scope that the transformation has been described as “click” chemistry. An overview of the mechanism of this … Abstract Cu I ‐catalyzed alkyne–azide cycloaddition provides 1,4‐disubstituted 1,2,3‐triazoles with such efficiency and scope that the transformation has been described as “click” chemistry. An overview of the mechanism of this remarkable reaction is presented as a means to explain the myriad of experimental results, particularly the various methods of catalyst generation, solvent and substrate effects, and choice of base or ligand. Both solution‐phase and solid‐phase results are comprehensively examined. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Activity-Based Protein Profiling: From Enzyme Chemistry to Proteomic Chemistry

2008-03-26

Benjamin F. Cravatt , Aaron Wright , John W. Kozarich

Genome sequencing projects have provided researchers with a complete inventory of the predicted proteins produced by eukaryotic and prokaryotic organisms. Assignment of functions to these proteins represents one of the … Genome sequencing projects have provided researchers with a complete inventory of the predicted proteins produced by eukaryotic and prokaryotic organisms. Assignment of functions to these proteins represents one of the principal challenges for the field of proteomics. Activity-based protein profiling (ABPP) has emerged as a powerful chemical proteomic strategy to characterize enzyme function directly in native biological systems on a global scale. Here, we review the basic technology of ABPP, the enzyme classes addressable by this method, and the biological discoveries attributable to its application.

Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality

2009-08-27

Ellen M. Sletten , Carolyn R. Bertozzi

The study of biomolecules in their native environments is a challenging task because of the vast complexity of cellular systems. Technologies developed in the last few years for the selective … The study of biomolecules in their native environments is a challenging task because of the vast complexity of cellular systems. Technologies developed in the last few years for the selective modification of biological species in living systems have yielded new insights into cellular processes. Key to these new techniques are bioorthogonal chemical reactions, whose components must react rapidly and selectively with each other under physiological conditions in the presence of the plethora of functionality necessary to sustain life. Herein we describe the bioorthogonal chemical reactions developed to date and how they can be used to study biomolecules.

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Applications of Orthogonal “Click” Chemistries in the Synthesis of Functional Soft Materials

2009-11-11

Rhiannon K. Iha , Karen L. Wooley , Andreas M. Nyström +3 more

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTApplications of Orthogonal "Click" Chemistries in the Synthesis of Functional Soft MaterialsRhiannon K. Iha†, Karen L. Wooley*†‡, Andreas M. Nyström§, Daniel J. Burke⊥, Matthew J. Kade⊥, and … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTApplications of Orthogonal "Click" Chemistries in the Synthesis of Functional Soft MaterialsRhiannon K. Iha†, Karen L. Wooley*†‡, Andreas M. Nyström§, Daniel J. Burke⊥, Matthew J. Kade⊥, and Craig J. Hawker*⊥View Author Information Department of Chemistry, Department of Radiology, Washington University in Saint Louis, Saint Louis, Missouri 63130, Department of Chemistry, Texas A&M University, College Station, Texas 77842, Cancer Center Karolinska, Department of Oncology-Pathology CCK, R8:03 Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden, and Department of Chemistry and Biochemistry, Department of Materials, and Materials Research Laboratory, University of California, Santa Barbara, California 93106* To whom correspondence should be addressed. E-mail addresses: [email protected]; [email protected]†Washington University in Saint Louis.‡Texas A&M University.§Karolinska Hospital and Institute.⊥University of California, Santa Barbara.Cite this: Chem. Rev. 2009, 109, 11, 5620–5686Publication Date (Web):November 11, 2009Publication History Received6 April 2009Published online11 November 2009Published inissue 11 November 2009https://pubs.acs.org/doi/10.1021/cr900138thttps://doi.org/10.1021/cr900138treview-articleACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views29488Altmetric-Citations1344LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Copolymers,Functionalization,Modification,Polymers,Radical polymerization Get e-Alerts

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Efficiency and Fidelity in a Click‐Chemistry Route to Triazole Dendrimers by the Copper(<scp>I</scp>)‐Catalyzed Ligation of Azides and Alkynes

2004-06-30

Peng Wu , Alina K. Feldman , Anne K. Nugent +7 more

Components that click: A large number of diverse dendrimers (see scheme) was prepared in almost quantitative yield by the click-chemistry transformation described in the title. In some cases filtration or … Components that click: A large number of diverse dendrimers (see scheme) was prepared in almost quantitative yield by the click-chemistry transformation described in the title. In some cases filtration or solvent extraction was the only method required for purification in this highly efficient construction of the triazole units of the dendrimers.

The growing impact of click chemistry on drug discovery

2003-12-01

Hartmuth C. Kolb , K. Barry Sharpless

Thiol–Ene Click Chemistry

2010-02-17

Charles E. Hoyle , Christopher N. Bowman

Abstract Following Sharpless′ visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these … Abstract Following Sharpless′ visionary characterization of several idealized reactions as click reactions, the materials science and synthetic chemistry communities have pursued numerous routes toward the identification and implementation of these click reactions. Herein, we review the radical‐mediated thiol–ene reaction as one such click reaction. This reaction has all the desirable features of a click reaction, being highly efficient, simple to execute with no side products and proceeding rapidly to high yield. Further, the thiol–ene reaction is most frequently photoinitiated, particularly for photopolymerizations resulting in highly uniform polymer networks, promoting unique capabilities related to spatial and temporal control of the click reaction. The reaction mechanism and its implementation in various synthetic methodologies, biofunctionalization, surface and polymer modification, and polymerization are all reviewed.

Kinetics and Mechanism of 1,3‐Dipolar Cycloadditions

1963-11-01

Rolf Huisgen

Abstract Criteria for the mechanism of 1,3‐dipolar cycloadditions which lead to 5‐membered rings are provided by the stereoselectivity observed with cis‐trans isomeric dipolarophiles, by the effect of solvent and substituents … Abstract Criteria for the mechanism of 1,3‐dipolar cycloadditions which lead to 5‐membered rings are provided by the stereoselectivity observed with cis‐trans isomeric dipolarophiles, by the effect of solvent and substituents on the rate constants, by the activation parameters, and by orientation phenomena. A concerted addition, which can also be described in terms of molecular orbitals and in which the two new σ‐bonds are formed simultaneously, although not necessarily at equal rates, offers the best explanation of the experimental facts.

1,3‐Dipolar Cycloadditions of Azides and Alkynes: A Universal Ligation Tool in Polymer and Materials Science

2007-01-09

Jean‐François Lutz

In 2001, Sharpless and co-workers introduced "click" chemistry, a new approach in organic synthesis that involves a handful of almost perfect chemical reactions. Among these carefully selected reactions, Huisgen 1,3-dipolar … In 2001, Sharpless and co-workers introduced "click" chemistry, a new approach in organic synthesis that involves a handful of almost perfect chemical reactions. Among these carefully selected reactions, Huisgen 1,3-dipolar cycloadditions were shown to be the most effective and versatile and thus became the prime example of click chemistry. Hence, these long-neglected reactions were suddenly re-established in organic synthesis and, in particular, have gained popularity in materials science. The number of publications dealing with click chemistry has grown exponentially over the last two years. The Minireview discusses whether click chemistry is a miracle tool or an ephemeral trend.

Advances in Chemical Protein Modification

2015-02-20

Omar Boutureira , Gonçalo J. L. Bernardes

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTAdvances in Chemical Protein ModificationOmar Boutureira*† and Gonçalo J. L. Bernardes*‡§View Author Information† Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n, … ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTAdvances in Chemical Protein ModificationOmar Boutureira*† and Gonçalo J. L. Bernardes*‡§View Author Information† Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n, 43007 Tarragona, Spain‡ Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom§ Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal*E-mail: [email protected]*E-mail: [email protected]; [email protected]Cite this: Chem. Rev. 2015, 115, 5, 2174–2195Publication Date (Web):February 20, 2015Publication History Received26 July 2014Published online20 February 2015Published inissue 11 March 2015https://doi.org/10.1021/cr500399pCopyright © 2015 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoicewith CC-BYlicenseArticle Views49821Altmetric-Citations768LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (5 MB) Get e-AlertsSUBJECTS:Chemical reactions,Hydrocarbons,Modification,Monomers,Peptides and proteins Get e-Alerts

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The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products

1981-01-01

Oyo Mitsunobu

Abstract The reagent formed by combining diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP) could be utilized in the intermolecular dehydration between an alcohol and various acidic components such as carboxylic acids, … Abstract The reagent formed by combining diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP) could be utilized in the intermolecular dehydration between an alcohol and various acidic components such as carboxylic acids, phosphoric diesters, imides, and active methylene compounds. By the use of DEAD and TPP, diols and hydroxy acids gave cyclic ethers and lactones, respectively. The reaction of nucleosides with DEAD and TPP afforded triphenylphosphoranylnucleosides. Alcohols reacted with 2,6-di-t-butyl-4-nitrophenol in the presence of DEAD and TPP to give aci-nitroesters which converted into the corresponding carbonyl compounds.

In situ click chemistry generation of cyclooxygenase-2 inhibitors

2017-02-09

Atul Bhardwaj , Jatinder Kaur , Melinda Wuest +1 more

Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible … Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

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Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

2018-02-05

Nicholas A. Meanwell

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, … The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Click Chemistry: Diverse Chemical Function from a Few Good Reactions

2001-06-01

Hartmuth C. Kolb , M. G. Finn , K. Barry Sharpless

Examination of nature's favorite molecules reveals a striking preference for making carbon–heteroatom bonds over carbon–carbon bonds—surely no surprise given that carbon dioxide is nature's starting material and that most reactions … Examination of nature's favorite molecules reveals a striking preference for making carbon–heteroatom bonds over carbon–carbon bonds—surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon–heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C−C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C−X−C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides

2005-10-28

Li Zhang , Xinguo Chen , Peng Xue +5 more

Cp*RuCl(PPh3)2 is an effective catalyst for the regioselective "fusion" of organic azides and terminal alkynes, producing 1,5-disubstituted 1,2,3-triazoles. Internal alkynes also participate in this catalysis, resulting in fully substituted 1,2,3-triazoles. Cp*RuCl(PPh3)2 is an effective catalyst for the regioselective "fusion" of organic azides and terminal alkynes, producing 1,5-disubstituted 1,2,3-triazoles. Internal alkynes also participate in this catalysis, resulting in fully substituted 1,2,3-triazoles.

Terminal alkyne formation by a pyridoxal phosphate-dependent enzyme

2025-06-25

Jason B. Hedges , Jorge A. Marchand , Carla Calvó‐Tusell +5 more | Nature Chemical Biology

Diethenyl Sulfoximine (DESI) as an Irreversible Lysine‐Targeting Warhead Enables the Design of Covalent Allosteric EGFR Inhibitor

2025-06-24

Huiqi Xu , Hongjin Zhang , Suyun Jia +7 more | Chemistry - A European Journal

Targeting lysine residues with covalent inhibitors is challenging due to their abundance in the proteome and the protonation of lysine's ε‐amino group, which diminishes its reactivity. This study introduces diethenyl … Targeting lysine residues with covalent inhibitors is challenging due to their abundance in the proteome and the protonation of lysine's ε‐amino group, which diminishes its reactivity. This study introduces diethenyl sulfoximine (DESI) as a novel bio‐orthogonal aminophilic electrophile which can react with lysine via double conjugate addition to form a cyclic adduct. The second addition promotes the entire and efficient electrophilic attack by the ε‐amino of lysine on the ethenyl groups. DESI exhibits superior aqueous stability, overcoming the hydrolysis issue encountered by most reported lysine‐targeting covalent agents. Incorporation of DESI in the allosteric pocket binder EAI045 of oncoprotein epidermal growth factor receptor (EGFR) yields compound 4, which specifically reacts to the catalytic lysine (Lys745). Compound 4 showed potent inhibition of EGFR‐driven cell proliferation with IC50 values of 0.789 µM and 1.22 µM in engineered BaF3‐EGFRL858R/T790M/C797S and NCI‐H1975 cells, respectively, overcoming EAI045's limitation of lack in cellular potency as a single agent. Tyrosine kinases panel profiling confirmed selectivity toward mutant EGFR while sparing the wild type with minimal off‐targets. These findings highlight DESI's potential as a versatile strategy for targeting lysine residues irreversibly, offering solutions to overcome drug resistance in cancer therapy and advance next‐generation precision medicines.

Bioorthogonal Click‐to‐Release of Branched Pro‐Fluorophores

2025-06-24

Thomasin K. Brind , Aggie Lawer , Travis P. Todd +3 more | Chemistry - A European Journal

Bioorthogonal click‐to‐release prodrug activation strategies should be fast and high yielding. However, in strain‐promoted alkene‐azide click‐to‐release, a fast click‐step translates to slow and inefficient drug release. To improve drug yield, … Bioorthogonal click‐to‐release prodrug activation strategies should be fast and high yielding. However, in strain‐promoted alkene‐azide click‐to‐release, a fast click‐step translates to slow and inefficient drug release. To improve drug yield, branched dual‐core scaffolds that increase drug release are reported. The dual‐core consists of an exposed electron‐deficient aryl azide (core‐1) attached to an electron‐rich self‐immolating branched linker (core‐2). Core‐1, a tetrafluoroaryl azide with methyl‐substitution at the benzylic carbon, facilitates a rapid click reaction with trans‐cyclooctenes (TCOs). Core‐2 had an N‐methyl carbamate or ether linker and a 1,4/1,4‐ or 1,4/1,6‐self‐immolating scaffold. Various release rates of a fluorophore were observed across the series, with 1,4/1,6‐self‐immolating core‐2, linked via the N‐methyl carbamate, having sustained and enhanced fluorophore release. The second order rate constant for cycloaddition of this 1,4/1,6‐self‐immolating analogue and d‐TCO is, to the best of our knowledge, the fastest to date (22.0 M‐1 s‐1). A persistent intermediate was observed, leading to a long, sustained release of fluorophore from the branched scaffold, though activation under acidic conditions (pH = 5.5) led to ≈15% higher fluorophore release compared to activation at pH 7.4. Therefore, combinations of core‐1 and core‐2 could improve future pre‐targeted in vivo bioorthogonal click‐to‐release prodrug strategies, especially in the acidic tumour environment.

(Photo)Biocatalytic Approach towards Radical Cross-Coupling Mediated by Thiamine Acting as NHC

2025-06-23

| Synfacts

Unexpected Isoxazole Recombination Photochemistry Unlocks Novel Bioorthogonal Pyrrole Synthesis

2025-06-23

| Synfacts

A biocompatible Lossen rearrangement in Escherichia coli

2025-06-23

Nick Johnson , Marcos Valenzuela-Ortega , Thomas W. Thorpe +4 more | Nature Chemistry

Nature has evolved an exquisite yet limited set of chemical reactions that underpin the function of all living organisms. By contrast, the field of synthetic organic chemistry can access reactivity … Nature has evolved an exquisite yet limited set of chemical reactions that underpin the function of all living organisms. By contrast, the field of synthetic organic chemistry can access reactivity not observed in nature, and integration of these abiotic reactions within living systems offers an elegant solution to the sustainable synthesis of many industrial chemicals from renewable feedstocks. Here we report a biocompatible Lossen rearrangement that is catalysed by phosphate in the bacterium Escherichia coli for the transformation of activated acyl hydroxamates to primary amine-containing metabolites in living cells. Through auxotroph rescue, we demonstrate how this new-to-nature reaction can be used to control microbial growth and chemistry by generating the essential metabolite para-aminobenzoic acid. The Lossen rearrangement substrate can also be synthesized from polyethylene terephthalate and applied to whole-cell biocatalytic reactions and fermentations generating industrial small molecules (including the drug paracetamol), paving the way for a general strategy to bioremediate and upcycle plastic waste in native and engineered biological systems.

Bidirectional Suzuki Catalyst Transfer Polymerization of Poly(p-phenylene)

2025-06-23

Christina M. Dadich , Felix R. Fischer | Macromolecules

Estimating the relative rates of lipopolysaccharide synthesis in Escherichia coli K-12 by click chemistry-mediated labeling

2025-06-23

Sheng Shu , Wei Mi | PLoS ONE

Lipopolysaccharide (LPS), a critical glycolipid component of Gram-negative bacteria, plays a central role in bacterial membrane integrity and host immune interactions. Despite extensive studies on the regulation of LPS synthesis, … Lipopolysaccharide (LPS), a critical glycolipid component of Gram-negative bacteria, plays a central role in bacterial membrane integrity and host immune interactions. Despite extensive studies on the regulation of LPS synthesis, methods to quantify its synthesis rate remain limited. Here, we present a novel approach to measure in vivo LPS synthesis rates in the E. coli K-12 strain MG1655 using click chemistry. This method involves the incorporation of an exogenous Kdo analog, 8-azido-3,8-dideoxy-D-manno-oct-2-ulosonic acid (Kdo-N3), into newly synthesized LPS, followed by a copper-free click reaction with a fluorescent alkyne. The labeled LPS is separated by SDS-PAGE and visualized via in-gel fluorescence. We compared two fluorescent dyes and found that AZDye 488 DBCO exhibited stronger sensitivity for labeling LPS during the log phase of bacterial growth. Our results further demonstrated that the amount of newly synthesized LPS correlates linearly with the pulse labeling time of Kdo-N3, validating this approach as a reliable method for estimating relative LPS synthesis rates during the exponential phase of E. coli MG1655 growth. This method offers a reliable, non-radioactive approach for measuring LPS synthesis in vivo, providing a powerful tool to investigate bacterial physiology and the regulation of LPS biogenesis.

Triclosan exposure potentiates ischemic stroke risk: Multi-omics integration and molecular docking unveil neurotoxic mechanisms

2025-06-21

Fangyuan Cheng , Han Gao , Bo Yan +2 more | Ecotoxicology and Environmental Safety

The Design and Application of Inhibiting Peptide for Rapid In vitro Downregulation of Post-Translational Modifications Levels at a Specific Site

2025-06-20

Shuping Zhang , Jiaqi Liu , Ning Su +4 more | Journal of Visualized Experiments

NHC‐based Photoswitches in Catalysis: Recent Developments and Challenges

2025-06-20

Gilles Alcaraz , Lucie Jarrige | European Journal of Organic Chemistry

Using light as an external stimulus, photoswitchable catalysis offers the attractive opportunities to modulate the activity and selectivity of catalytic systems on demand and remotely, with high spatial and temporal … Using light as an external stimulus, photoswitchable catalysis offers the attractive opportunities to modulate the activity and selectivity of catalytic systems on demand and remotely, with high spatial and temporal precision. Consequently, the development of photoswitchable catalyst has attracted considerable attention from the chemist community in recent decades, leading to various photoresponsive species with diverse properties. Among these, only a few examples incorporate N‐heterocyclic carbenes (NHCs), despite their unique electronic and steric properties and their ubiquity in organic and organometallic catalysis. This review highlights recent advances in this emerging research area from the first reported species in 2009 to the present day, with particular emphasis on the synthesis of photoswitchable NHCs and their corresponding transition metal complexes for application in catalysis. Future perspectives in the field are also discussed.

Exploring Natural Coumarins: Breakthroughs in Anticancer Therapeutics

2025-06-19

Emine Terzi , Beyza Ecem Oz-Bedir , Jean‐Yves Winum | Anti-Cancer Agents in Medicinal Chemistry

Abstract: Natural coumarins, a class of compounds found abundantly in various plants, are emerging as promising candidates in fight against cancer. Their ability to target multiple cancer-related processes has drawn … Abstract: Natural coumarins, a class of compounds found abundantly in various plants, are emerging as promising candidates in fight against cancer. Their ability to target multiple cancer-related processes has drawn significant interest from researchers. Natural coumarins exhibit anticancer effects through mechanisms such as inducing apoptosis, which is the programmed death of cancer cells, inhibiting cell proliferation, and disrupting angiogenesis, the process by which tumors develop their own blood supply to sustain growth. What makes coumarins particularly intriguing is their broad-spectrum activity against various types of cancer cells, from breast to lung to colon cancers. They interact with key molecular pathways that drive tumor progression, making them versatile agents in cancer therapy. Additionally, unlike many conventional chemotherapy drugs, natural coumarins generally have lower toxicity, which could translate to fewer side effects for patients. This characteristic makes them attractive as potential standalone treatments or as complementary therapies that enhance the efficacy of existing drugs while minimizing harm to normal cells. Ongoing research continues to explore the therapeutic potential of natural coumarins to better understand their full therapeutic potential and how they might work in combination with other anticancer agents. As the body of evidence grows, these natural compounds could become integral components of more effective and less harmful cancer treatment regimens, offering new hope for patients facing this challenging disease. This review was conducted by systematically analyzing the existing literature on natural coumarins and their anticancer potential.

Click biology highlights the opportunities from reliable biological reactions

2025-06-19

Mark Howarth | Nature Chemical Biology

Design, Synthesis, Antimicrobial Evaluation and In Silico Studies of Novel Indole Clubbed Pyrazole Linked 1,2,3‐Triazole Derivatives

2025-06-19

Monil P. Dholariya , Anil S. Patel | Journal of Heterocyclic Chemistry

ABSTRACT A series of novel indole–pyrazole–triazole hybrids (6a–o) was synthesized using a copper(I)‐catalyzed azide‐alkyne cycloaddition (click chemistry) under microwave irradiation. The target compounds were obtained in good yields from readily … ABSTRACT A series of novel indole–pyrazole–triazole hybrids (6a–o) was synthesized using a copper(I)‐catalyzed azide‐alkyne cycloaddition (click chemistry) under microwave irradiation. The target compounds were obtained in good yields from readily available, low‐cost starting materials under simple reaction conditions. Structural confirmation of the synthesized compounds was achieved using 1 H NMR, 13 C NMR, IR, and mass spectrometry. The synthesized hybrids were then evaluated for their in vitro antimicrobial activity against bacterial strains Bacillus subtilis , Staphylococcus aureus , Escherichia coli , Pseudomonas aeruginosa , and fungal strains Aspergillus niger and Candida albicans . Among all the compounds, 6b , 6j , 6m , and 6o demonstrated potent antibacterial activity comparable to the standard drug Chloramphenicol, while compounds 6j and 6n showed superior antifungal activity compared to Nystatin. The most active compounds were further analyzed through molecular docking studies using Autodock, targeting DNA gyrase (PDB ID: 1KZN) and sterol 14α‐demethylase (PDB ID: 5TZ1) proteins. Additionally, ADME properties were assessed to evaluate the pharmacokinetic potential of all synthesized compounds.

Primary Amine-Based Photoclick Chemistry: From Concept to Diverse Applications in Chemical Biology and Medicinal Chemistry

2025-06-18

Hao Hu , Hui-Jun Nie , Xiaohua Chen | Accounts of Chemical Research

ConspectusClick chemistry has significantly impacted many fields. The emergence of photoclick chemistry, which harnesses light-driven processes under mild conditions, has introduced distinct advantages, including precise spatiotemporal control, high selectivity, and … ConspectusClick chemistry has significantly impacted many fields. The emergence of photoclick chemistry, which harnesses light-driven processes under mild conditions, has introduced distinct advantages, including precise spatiotemporal control, high selectivity, and elimination of toxic metal catalysts and reagents. These features make photoclick chemistry a highly valuable tool in various fields. Although many exciting applications have been found, the development of photoclick methodologies remains limited, and photoclick chemistry is still in its early stage. Thus, the development of novel and versatile systems is crucial for advancing a wide range of applications and fully realizing their potential.In this Account, we aim to highlight the concept of a novel photoclick chemistry, light-induced Primary Amine and o-Nitrobenzyl Alcohol Cyclization (PANAC), to broaden the potential and applications of photoclick chemistry. Inspired by the abundance and versatility of primary amines in synthetic chemistry, biological systems, and materials science, we introduced the primary amine as a direct and general photoclick handle, while the o-nitrobenzyl alcohol (o-NBA) structure was designed as a molecular plugin to provide easily accessible and modular reactants for the PANAC photoclick reaction. With intrinsic features such as temporal control, reliable chemoselectivity, high efficiency, readily accessible reactants, biocompatibility, operational simplicity, and mild conditions, the developed PANAC photoclick reaction aligns with the core criteria of photoclick chemistry. By leveraging the advantages of PANAC photoclick chemistry and designing various conjugation strategies, we have successfully applied it in various applications, enabling modular synthesis and bioconjugation, including modular functionalization of bioactive small molecules, lysine-specific unprotected peptide cyclization and labeling of native proteins both in vitro and in live cells, and temporal profiling of endogenous kinases and organelle-targeted labeling in living systems. Moreover, by harnessing widespread primary amines and the versatility of PANAC photoclick chemistry, we developed a direct-to-biology platform for proteolysis-targeting chimera (PROTAC) library assembly, accelerating PROTAC degrader discovery, and created structurally diverse DNA-encoded libraries for high-throughput screening and identification of novel bioactive compounds. Furthermore, based on primary-amine-based modular synthesis, a general platform for the efficient and modular assembly of ligand-oligonucleotide conjugations via PANAC photoclick chemistry enables rapid access to therapeutic oligonucleotides. More importantly, PANAC photoclick chemistry enables temporally controlled proteome-wide profiling of biomacromolecule interactions and dynamics through endogenous lysine bioconjugation within complex biological environments. This is exemplified by the spatiotemporal and global profiling of DNA-protein interactions, which enables the discovery of low-affinity transcription factors, as well as by the direct capture of protein-protein interactions (PPIs) and global substrates of lysine-modifying enzymes in live cells, thereby providing a valuable tool for exploring previously unrecognized functional roles of proteins.Collectively, with its versatility and high efficiency, PANAC photoclick chemistry has emerged as an accessible and promising chemical tool across diverse fields. Building on its intrinsic advantages and potential for future development, PANAC photoclick chemistry will open up exciting opportunities for the functional discovery of primary-amine-enabled photoclick connections and inspire innovative solutions to address challenges in areas such as synthetic chemistry, medicinal chemistry, chemical biology, and materials science.

Other edens

2025-06-18

Neil Drabble , Rose Gridneff | RIBA Publishing eBooks

Fluorescent Isostere (Fluostere) of the Carboxylate: Design of hDHODH Fluorescent Inhibitors as Proof of Concept

2025-06-18

Stefano Sainas , Elena Martino , Claudio Garino +7 more | Journal of Medicinal Chemistry

Fluorescent probes targeting proteins are used to investigate biological processes, requiring strong binding affinity and favorable fluorescence. In this study, we present the first fluostere with optimized fluorescence properties. We … Fluorescent probes targeting proteins are used to investigate biological processes, requiring strong binding affinity and favorable fluorescence. In this study, we present the first fluostere with optimized fluorescence properties. We started exploring the fluorescence of acidic pyrazolo[1,5-a]pyridin-2-ol, and, by the introduction of EWGs, π-conjugation, incorporation of push-pull systems and rigid structures, we optimized emission profiles and QY, providing a first Structure-Fluorescence relationship (SFR) of the system. To provide proof of concept in biological applications, the established SFR was integrated with hDHODHi, an important oncology target, enabling the SAR designing fluorescent hDHODHi 11a and 14, with 11a being the most potent IC50 = 170 nM. These inhibitors were validated in vitro for their antileukemic and antiviral activity. As they are both environmentally sensitive fluorescent probes that can highlight their binding to the target, their fluorescence was found to colocalize in the mitochondria, where hDHODH is located, in cellular experiments.

Cu/Ru Sequential Catalysis via In Situ Directing Group Formation for Site‐Selective CH Arylation

2025-06-17

Yu‐Yong Luan , Jinye Li , Xiaoping Gong +2 more | Advanced Synthesis & Catalysis

A Cu/Ru bimetallic sequential catalytic strategy combining copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) with Ru‐catalyzed CH activation is developed, enabling the in situ formation of nitrogen‐containing triazoles and their ortho CH arylation … A Cu/Ru bimetallic sequential catalytic strategy combining copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) with Ru‐catalyzed CH activation is developed, enabling the in situ formation of nitrogen‐containing triazoles and their ortho CH arylation in a one‐pot dual‐functional transformation. This system innovatively employs the 1,2,3‐triazole formed via CuAAC as an endogenous directing group, facilitating sequential [3+2] cycloaddition and Ru‐mediated CH functionalization through a stepwise catalytic approach. The strategy overcomes the limitations of traditional preactivation and exhibits excellent regioselectivity and broad substrate compatibility. This approach has been successfully applied to the late‐stage modification of pharmaceutical molecules, offering a new paradigm for the modular synthesis of complex compounds.

Regiodivergent Annulation Reactions of Chalcones to Indenones and Indanones with C1 Reagents

2025-06-17

Xinchi Gong , Sunewang Rixin Wang | The Journal of Organic Chemistry

One-pot direct regiodivergent annulations of chalcones, as exemplified by the drug metochalcone and a bioactive dichloro-substituted chalcone with a quinoline ring, to indanones and indenones are conveniently achieved with single-carbon … One-pot direct regiodivergent annulations of chalcones, as exemplified by the drug metochalcone and a bioactive dichloro-substituted chalcone with a quinoline ring, to indanones and indenones are conveniently achieved with single-carbon reagent Kukhtin-Ramirez adducts. A Cs2CO3-promoted unusual selective cleavage of the cyclopropyl C-C bond distal to the strong carbonyl acceptor, further driven to completion by follow-up regiodivergent annulations via Pd(OAc)2-catalyzed Heck reaction or Cs2CO3-mediated SNAr process, is key for the success.

Subcellular Analysis of Fatty Acid Metabolism Using Organelle-Selective Click Chemistry

2025-06-17

Takeshi Kimura , Seiji Kawamoto , Alma Fujisawa +5 more | Journal of the American Chemical Society

The structural diversity of the fatty acids esterified in organellar membrane lipids is thought to confer the characteristic physiological properties of the membranes. However, the abundance profiles of fatty acid … The structural diversity of the fatty acids esterified in organellar membrane lipids is thought to confer the characteristic physiological properties of the membranes. However, the abundance profiles of fatty acid derivatives are still poorly characterized at organelle-level spatial resolution. Here, we have developed a technology for organelle-specific labeling and quantitative analysis of fatty acid derivatives involving the metabolic incorporation of azide fatty acids and organelle-localizing clickable dyes. This approach was used to investigate palmitate- and oleate-derived lipids in different organelle membranes. The relative abundances of fatty acid-containing lipids were found to differ depending on the organelle and the structure of the fatty acid. In addition, organelle-specific temporal variations in fatty acid derivatives were revealed that are difficult to detect using conventional lipid analysis.

Biodialyzed Palladium catalysis enables bioorthogonal drug release to control epithelial progenitor cell differentiation

2025-06-17

Asier Unciti‐Broceta , Rafael Contreras‐Montoya , Cecilia Rocchi +7 more | Research Square (Research Square)

<title>Abstract</title> Flowing from the principles of bioorthogonality, the introduction of abiotic transition metals for the catalytic production of drugs at specific anatomical locations has carved new paths to face challenging … <title>Abstract</title> Flowing from the principles of bioorthogonality, the introduction of abiotic transition metals for the catalytic production of drugs at specific anatomical locations has carved new paths to face challenging diseases, including cancer. Despite ground-breaking advances in this area, the main barrier for the long-term application of bioorthogonal catalysis in medicine is catalyst inactivation by the surrounding environment. Herein we present a semipermeable membrane-inspired approach to separate the catalysts from the environment by incorporating them into a porous scaffold that minimizes interactions with surrounding biomolecules. Cross-linked lysozyme crystals of controlled size were functionalized with Pd(II) and reduced to Pd(0), operating as a size exclusion barrier for large macromolecules while enabling the traffic and chemical conversion of small molecule substrates with excellent efficiency, recyclability and tolerability. The capabilities of this catalytic system were harnessed ex vivo in salivary gland tissue to achieve epithelial progenitor cell differentiation by drug uncaging. This work provides a truly biocompatible strategy to extend catalytic processing and expands the scope of the field towards a new frontier: regenerative medicine.

Imidazol‐2‐Ylidene‐Silver(I) Complexes Bearing 4‐Acetylphenyl Side Arm: Design, Synthesis, Characterization, Crystal Structure, and Inhibitory Properties Against Some Metabolic Enzymes

2025-06-16

Özlem Demirci , Yeliz Demir , Yetkın Gök +6 more | Applied Organometallic Chemistry

ABSTRACT Herein, the synthesis of silver(I)‐ N ‐heterocyclic carbene (Ag(I)NHC) complexes is presented. These complexes were synthesized from imidazolium salts and silver oxide via the deprotonation method. Ag(I)NHC complexes were … ABSTRACT Herein, the synthesis of silver(I)‐ N ‐heterocyclic carbene (Ag(I)NHC) complexes is presented. These complexes were synthesized from imidazolium salts and silver oxide via the deprotonation method. Ag(I)NHC complexes were characterized using various spectroscopic and analytical techniques, including FTIR, NMR, and elemental analysis. The single crystal structures of the complexes 1e and 1g were illuminated through x‐ray crystallography. The study demonstrates that the geometrical characteristics of both complexes closely match those of previously described complexes with a comparable ligand structure. Acetylcholinesterase (AChE) inhibitors prevent the excessive breakdown of acetylcholine by acting on acetylcholinesterase in its neurotransmission. In this way, they help to improve cognitive functions in patients with AD. On the other hand, human carbonic anhydrase inhibitors (CAIs) have been used clinically for many years as antiepileptic, antiglaucoma, antimetastatic, antitumor, and diuretic agents. In this study, the enzyme inhibition abilities of seven imidazol‐2‐ylidene‐silver(I) complexes bearing 4‐acetylphenyl side arm were examined against AChE and hCAs. These molecules exhibited a highly potent inhibition effect on AChE and hCAs (K i values are in the range of 16.27 ± 1.81 to 130.79 ± 11.98 nM for AChE, 13.22 ± 1.88 to 182.14 ± 33.93 nM for hCA I, and 12.72 ± 1.99 to 62.36 ± 9.21 nM for hCA II). Novel imidazol‐2‐ylidene‐silver(I) complexes bearing 4‐acetylphenyl side arms 1a–g displayed efficient inhibitory profiles for the examined metabolic enzymes. Docking was additionally performed to investigate the interactions of the current complexes 1a–g with hCA I, hCA II, and AChE proteins. It has been determined that compound 1d has activity against all the tested proteins, with the most effective interaction observed with hCA I. The pharmacokinetic properties of the three top potent complexes for each target against the related proteins were also examined using the SwissADME and pkCSM web tools. In the meantime, the stabilities of the complexes with the highest binding potential according to the docking study were assessed through molecular dynamics simulation. The AChE– 1a complex was found to be the one with relatively high stability. Also, further energy computations were made by using the MD simulation results. The compounds have been estimated to bind strongly with their targets.

Multiphoton Multicomponent Reactions: Discovery of the 2‐Photon Ketene 4‐Component Reaction (2P‐K‐4CR)

2025-06-16

Federica Minuto , Martina Buccioli , Pietro Capurro +5 more | Advanced Synthesis & Catalysis

Herein, the first multiphoton, multicomponent approach for synthesizing highly functionalized oxetanes using diazoketones, isocyanides, silanols (or carboxylic acids), and 1,2‐dicarbonyl derivatives (benzils) is presented as starting materials. Blue light irradiation … Herein, the first multiphoton, multicomponent approach for synthesizing highly functionalized oxetanes using diazoketones, isocyanides, silanols (or carboxylic acids), and 1,2‐dicarbonyl derivatives (benzils) is presented as starting materials. Blue light irradiation initiates the Wolff rearrangement of diazoketones, generating ketenes that promptly react with isocyanides and silanols (or carboxylic acids) to afford captodative olefins. Concurrently, excitation of benzils promotes a [2 + 2] photocycloaddition between the activated carbonyl group and the captodative olefin. This newly developed two‐photon ketene four‐component reaction has been thoroughly investigated, also through chemometric analysis, including its substrates scope and the extension to mixed benzils. Furthermore, the observed stereochemical outcomes, validated by X‐Ray diffraction analysis, are elucidated through detailed computational studies, providing insights into the underlying reaction mechanism.

Acridine-Based Fluorescent Probes

2025-06-16

Dheeraj Pandey , Abha Sharma | CRC Press eBooks

Benzothiazole-Based Fluorescent Probes for Various Applications

2025-06-16

Raviraj Bhatia , Preeti Ashokkumar Chaudhran , Abha Sharma | CRC Press eBooks

Design, synthesis, in-vivo, and in-silico studies of 1,2,3-triazole tethered derivatives of morphine as novel anti-nociceptive agents

2025-06-16

Faeze Nourmandipour , Reihane Emadi , Peyman Salehi +4 more | PLoS ONE

Due to the use of morphine as a well-known analgesic, a semi-synthesis of its newer triazole derivatives was performed in this project. Several derivatives were analyzed via molecular docking and … Due to the use of morphine as a well-known analgesic, a semi-synthesis of its newer triazole derivatives was performed in this project. Several derivatives were analyzed via molecular docking and a set of target molecules with acceptable docking scores were selected for the synthesis. The project focused on targeting one of the pharmacophores of morphine. The phenolic hydroxy group of morphine was reacted with propargyl bromide to furnish the terminal alkyne. This compound, as starting material for the click reaction underwent 1,3-dipolar cycloaddition reaction with different azides to produce the target 1,2,3-triazole tethered derivatives of morphine. The anti-nociceptive properties of the products were evaluated by tail flick test. It was observed that compounds 3b , 3d , and 3k with (ED 50 = 0.23 mg/kg) showed superior pain relief activities in comparison with morphine (ED 50 = 0.69 mg/kg). Finally, computational ADME/T studies were performed via SwissADME web server to gain a better understanding of the pharmacokinetics of the synthesized compounds in humans.

Switchable Reaction of p‐Toluenesulfonyl Hydrazide With N‐Heteroaryl Ketones: Base‐Controlled Selective Synthesis of N‐Heteroaryl Alcohols and [1, 2, 3]‐Triazoloheteroarenes

2025-06-16

Yifei Wu , Rurong Yu , Feiyue Hao +2 more | Asian Journal of Organic Chemistry

Abstract A novel switchable reaction of p ‐toluenesulfonyl hydrazide with N ‐heteroaryl ketones has been developed to synthesize N ‐heteroaryl alcohols and [1, 2, 3]‐triazoloheteroarenes. p ‐Toluenesulfonyl hydrazide was found … Abstract A novel switchable reaction of p ‐toluenesulfonyl hydrazide with N ‐heteroaryl ketones has been developed to synthesize N ‐heteroaryl alcohols and [1, 2, 3]‐triazoloheteroarenes. p ‐Toluenesulfonyl hydrazide was found to be an efficient reducing agent for N ‐heteroaryl ketones in the presence of Et 3 N. A cascade cyclization reaction occurred when NaOH was applied as a base.

Development of a First-in-Class Click Chemistry–Based Cancer Therapeutic, from Preclinical Evaluation to a First-in-Human Dose Escalation Clinical Trial

2025-06-16

Sangeetha Srinivasan , Nathan K. Yee , Maša Alečković +7 more | Clinical Cancer Research

Abstract Purpose: Achieving precise drug activation without associated toxicities is a significant challenge in developing cancer therapeutics. Click Activated Protodrugs Against Cancer is a pretargeting approach that uses bioorthogonal click … Abstract Purpose: Achieving precise drug activation without associated toxicities is a significant challenge in developing cancer therapeutics. Click Activated Protodrugs Against Cancer is a pretargeting approach that uses bioorthogonal click chemistry in vivo to selectively capture and activate drugs at tumors and can be applied to a wide variety of targeted therapeutics. The first-in-class Click Activated Protodrugs Against Cancer–based cancer therapeutic SQ3370 uses a clickable pretargeting agent that reacts with a chemically attenuated clickable payload of doxorubicin (Dox) and releases the active cytotoxic drug in situ. Patients and Methods: We describe the preclinical development and translation of SQ3370 to a first-in-human dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492). Results: SQ3370 inhibited tumor progression across several mouse tumor models through the safe and selective release of Dox in tumors at concentrations unachievable by conventional treatment. SQ3370 exhibited safety when administered at 8.9 times the veterinary Dox dose in dogs and 15 times the conventional Dox dose in patients, with no reported protocol-defined dose-limiting toxicities. In patients, SQ3370 modulated active Dox pharmacokinetics and enabled T-cell–dependent immune responses, including cytotoxic CD8+ T-cell expansion and activation in tumors and systemically. Conclusions: SQ3370, the first demonstration of click chemistry within the human body in a clinical setting, facilitated the delivery of chemotherapy to tumors and unlocked additional biological effects such as favorable immune responses that may benefit patients with metastasis. Consistent safety, toxicology, pharmacokinetic, and immune activation results observed across species highlight the translatability of the technology and position click chemistry as a powerful new modality for the development of targeted cancer therapeutics.

Click-Triggered Bioorthogonal Bond-Cleavage Reactions

2025-06-14

Patrick Keppel , Sebastian Hecko , Hannes Mikula | Topics in Current Chemistry

Abstract Bioorthogonal bond-cleavage reactions have evolved into powerful tools for chemical biology, representing a promising strategy for achieving controlled release of molecules under physiologically relevant conditions, even in living organisms. … Abstract Bioorthogonal bond-cleavage reactions have evolved into powerful tools for chemical biology, representing a promising strategy for achieving controlled release of molecules under physiologically relevant conditions, even in living organisms. Since their discovery, significant efforts have been invested in the development and understanding of the underlying chemistries to enhance the click-to-release performance, biocompatibility, and stability of bioorthogonal tools. In this review, we aim to provide a concise overview of click-triggered bioorthogonal bond-cleavage reactions, with an emphasis on the mechanisms and characteristics of the most commonly applied click-to-release chemistries.

Abstract P3-09-29: A Novel BBB-permeable Agent for Breast Cancer Brain Metastases

2025-06-13

Mariana K. Najjar , Daniel Doheny , Sara G. Manore +4 more | Clinical Cancer Research

Abstract Metastatic breast cancer is the second leading cause of cancer-related deaths among American women. The most common sites of breast cancer metastases are the bones, lungs, brain, and liver. … Abstract Metastatic breast cancer is the second leading cause of cancer-related deaths among American women. The most common sites of breast cancer metastases are the bones, lungs, brain, and liver. Among the different sites, breast cancer brain metastasis (BCBM) constitutes approximately 10-30% of metastatic breast cancer and is associated with worst dismal prognoses, with a median survival time of 7.9 months. The poor outcomes are attributed to the limited understanding of the driving factors of BCBM and the scarcity of drugs that can cross the blood-brain barrier (BBB) and blood-tumor barrier (BTB). This underscores the critical need to develop new therapies for BCBM. Our lab identified truncated glioma-associated oncogene homolog 1 (tGLI1) as an alternatively spliced, gain-of-function, tumor-specific variant of GLI1. Since its discovery, tGLI1 has been reported to promote breast cancer stem cells (CSC) and breast cancer preferential metastasis to the brain. Additionally, we recently identified the FDA-approved antifungal ketoconazole to selectively target tGLI1-positive breast cancer cells in vitro. Ketoconazole was also found to prevent the preferential metastasis of tGLI1-positive breast cancer to the brain and suppress the progression of established tGLI1-positive BCBM in vivo (Doheny et al., Cancers 14:4256, 2022). Ketoconazole is a potent inhibitor of the cytochrome P450 enzyme CYP3A4 and has been associated with liver damage, adrenal insufficiency, and drug interactions. To mitigate this issue with potential toxicities, we modified the chemical moieties of ketoconazole and generated novel derivatives. We screened the compounds using isogenic brain-tropic breast cancer cell lines engineered to stably express the vector, GLI1, or tGLI1 and identified the novel derivative WF-229A to selectively target tGLI1-positive breast cancer stem cells. Foremost, our data shows that WF-229A lost the ability to inhibit CYP3A4 enzymatic activity in vitro. Additionally, WF-229A showed no toxic effects on normal brain cells (astrocytes) or the liver cells (HepG2). In efforts to evaluate the pharmacological properties of WF-229A, we conducted an in vivo maximum tolerated dose (MTD) study. Our results demonstrated that, unlike ketoconazole, increasing doses of WF-229A did not elevate serum alanine transaminase (ALT) levels, indicating no liver toxicity. Additionally, increasing doses of WF-229A did not cause an increase in serum Adrenocorticotropic hormone (ACTH) levels suggesting, no adrenal insufficiency, unlike ketoconazole. Furthermore, our experimental mouse metastasis study using intracardiac inoculation demonstrated that systemic administration of WF-229A suppressed the progression of tGLI1-positive BCBM. WF-229A can penetrates the BBB in mice. For further characterization of WF-229A, we conducted a cellular thermal shift assay (CETSA) and found that WF-229A directly binds to tGLI1 protein, but not GLI1. Additional mechanistic studies showed that WF-229A suppresses the CD44+/CD24- stem cell population, hampers migration, and induces apoptosis in tGLI1-positive BCBM cells. Our study establishes the rationale to further characterize the pharmacological properties of WF-229A for fine-tuned targeting of BCBM, and to examine WF-229A’s ability to offer additional therapeutic benefits including the prevention of BCBM in vivo. Citation Format: Mariana K. Najjar, Daniel Doheny, Sara Manore, Chuling Zhuang, Munazza Samar Khan, Terrence Smalley, Hui-Wen Lo. A Novel BBB-permeable Agent for Breast Cancer Brain Metastases [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-29.

Abstract P3-08-29: Early Clinical Experience with TTX-MC138, a First-in-Class Therapeutic Candidate for Metastatic Breast Cancer

2025-06-13

Zdravka Medarova , Neil Robertson , Subrata Ghosh +7 more | Clinical Cancer Research

Abstract For the past 20 years our research has specifically focused on developing potential therapies targeting specific properties of tumor cells that have metastasized. Although the mechanisms and triggers of … Abstract For the past 20 years our research has specifically focused on developing potential therapies targeting specific properties of tumor cells that have metastasized. Although the mechanisms and triggers of metastasis are not completely understood, cancer cells exhibit the ability to break out of the primary tumor mass, travel through the circulation, and colonize a new vital organ in the process of metastasis. Of therapeutic significance, these metastatic cells are genetically and phenotypically distinct from the majority of the cells in the tumor mass serving to limit the effectiveness of those therapies whose focus is the primary tumor itself. In our earlier discovery efforts, miRNA-10b was identified as a master regulator of the viability of metastatic tumor cells. miRNA-10b not only promotes the capacity of tumor cells to migrate and invade surrounding tissue (become metastatic) but, most notably, serves as a powerful master regulator of the viability of these cells and their capacity to survive outside of the primary tumor microenvironment. Detailed cellular and preclinical mechanistic studies confirmed the existence of a miR-10b-triggered pathway that regulates the viability and proliferation of tumor cells only after they have acquired the ability to metastasize. This knowledge allowed us to develop a therapeutic strategy based on miR-10b inhibition. The specific inhibition of miR-10b was achieved using inhibitory oligonucleotides (locked nucleic acid, LNA-based antagomirs) delivered to metastatic sites by aminated dextran-coated iron oxide nanoparticles (termed TTX-MC138). Our research demonstrated that TTX-MC138 could cause complete and persistent regression of metastases in cancer models with no evidence of systemic toxicity. On the path to clinical development of TTX-MC138, we conducted critical, exploratory IND enabling studies in rats, dogs, and non-human primates with TTX-MC138. Ultimately, the information generated resulted in FDA authorization under IND163800 allowing for initiation of an ongoing microdosing Phase 0 clinical trial in patients with advanced metastatic cancer. The strategy of conducting an initial Phase 0 study was not only to assist in the identification of susceptible tumor types (or patients) but also to support future clinical efforts by providing proof of concept and quantification of delivery to clinical metastases. The Phase 0 clinical trial involves a single injection of a microdose of Cu-64 labeled TTX-MC138 which allows for direct visualization in cancer patients via PET-MR imaging, with a primary endpoint of confirming its localization (%ID/cc) to the metastatic lesions. We have now obtained initial clinical data on drug PK and accumulation in clinical metastases to the lungs, bone, and liver, as well as drug stability, metabolism, and pharmacodynamic activity. We have demonstrated TTX-MC138 uptake by bone, lung, and liver metastases, as well as tumor to blood ratios reflective of selective retention of the drug by tumor tissue. We have established that the drug has a long circulation time of 20 hrs in humans. Remarkably, even at a 100 microgram microdose, the drug showed robust PD activity with a 70% inhibition of the miR-10b target in blood over the full time course of the study. The process leading to the implementation of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX delivery platform to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Citation Format: Zdravka Medarova, Neil Robertson, Subrata Ghosh, Hsiao-Ying Wey, Mariane LeFur, Onofrio Catalano, Ciprian Catana, Peter Caravan, Susan Duggan, Andreas Varkaris. Early Clinical Experience with TTX-MC138, a First-in-Class Therapeutic Candidate for Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-29.

Abstract P3-08-30: Development of humanized anti-FABP4 monoclonal antibodies for potential treatment of breast cancer

2025-06-13

Bing Li | Clinical Cancer Research

Abstract Breast cancer is the most common cancer in women diagnosed in the U.S. and worldwide. Obesity increases breast cancer risk without clear underlying molecular mechanisms. Our studies demonstrate that … Abstract Breast cancer is the most common cancer in women diagnosed in the U.S. and worldwide. Obesity increases breast cancer risk without clear underlying molecular mechanisms. Our studies demonstrate that circulating adipose fatty acid binding protein (A-FABP, or FABP4) links obesity-induced dysregulated lipid metabolism and breast cancer risk, thus potentially offering a new target for breast cancer treatment. We immunized FABP4 knockout mice with recombinant human FABP4 and screened hybridoma clones with specific binding to FABP4. The potential effects of antibodies on breast cancer cells in vitro were evaluated using migration, invasion, and limiting dilution assays. Tumor progression in vivo was evaluated in various types of tumorigenesis models including C57BL/6 mice, Balb/c mice, and SCID mice. We identified over 30 clones which specifically bound to FABP4. One clone, named 12G2, was shown to significantly inhibit mammary tumor growth. After further confirming the therapeutic efficacy of the chimeric 12G2 monoclonal antibody consisting of mouse variable regions and human IgG1 constant regions, 16 humanized 12G2 monoclonal antibody variants were generated by grafting its complementary determining regions to selected human germline sequences. Humanized V9 monoclonal antibody showed consistent results in inhibiting mammary tumor growth and metastasis by affecting tumor cell mitochondrial metabolism. Thus, our data suggest that targeting FABP4 with humanized monoclonal antibodies represents a novel strategy for the treatment of breast cancer and possibly other obesity-associated diseases. Citation Format: Bing Li. Development of humanized anti-FABP4 monoclonal antibodies for potential treatment of breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-30.

Abstract P4-10-21: Enhanced anti-tumor activity of zelenectide pevedotin in triple negative breast cancer (TNBC) patients (pts) with NECTIN4 gene amplification (amp)

2025-06-13

Niklas Klümper , Viktor Grünwald , Johannes Brägelmann +7 more | Clinical Cancer Research

Abstract Background: Zelenectide pevedotin (zele, formerly BT8009) is a highly selective Bicycle® Toxin Conjugate (BTC) comprised of a bicyclic peptide targeting Nectin-4 conjugated to monomethyl auristatin E. BTC® molecules have … Abstract Background: Zelenectide pevedotin (zele, formerly BT8009) is a highly selective Bicycle® Toxin Conjugate (BTC) comprised of a bicyclic peptide targeting Nectin-4 conjugated to monomethyl auristatin E. BTC® molecules have lower molecular weight and shorter plasma half-life than antibody-drug conjugates, with distinct pharmacokinetics/dynamics, i.e., potential for rapid tumor penetration and minimal healthy tissue exposure. NECTIN4 amp has been shown to be a predictive biomarker for response to Nectin-4 targeted therapy in metastatic urothelial cancer (Klümper et al., 2024). An analysis of NECTIN4 amp in a large, independent sample of 245 breast cancer (BC) pts indicates that amp is common, seen in 19% (30/161), 14% (5/36) and 23% (11/48) of HR+/HER2-, HER2+ and TNBC, respectively (Klümper et al., unpublished data). This initial post-hoc analysis assesses the utility of NECTIN4 amp as a predictor of zele response in heavily pretreated BC pts. Methods: Zele is being evaluated in the ongoing Phase 1/2 study BT8009-100/Duravelo-1 (NCT04561362) for safety and efficacy in pts with advanced solid tumors associated with Nectin-4 expression including BC pts. This analysis focuses on TNBC study pts who had baseline tissue sample available, had consented to optional future research, and tested for NECTIN4 amp by fluorescence in-situ hybridization. NECTIN4 amp positivity was defined as a ratio of NECTIN4: centromere 1 (CEN1) of 2.0 or higher. Assessment of anti-tumor activity was per RECIST v1.1 by investigator. Objective response rate (ORR) is based on the efficacy evaluable population. Results: As of 29 August 2024, 32 heavily pretreated pts with TNBC enrolled in the monotherapy dose escalation and expansion cohorts of BT8009-100. Thirty-one TNBC pts were treated with the zele recommended Phase 2 dose of 5 mg/m2 weekly. At baseline, TNBC pts had a median age of 52 (30-76), median prior lines of therapy of 6 (2-13), and ECOG of 0 or 1 (50.0% each). Of 32 enrolled TNBC pts treated with zele, 30 were efficacy evaluable. Four pts achieved partial response (PR) resulting in an ORR of 13.3% (95% CI: 3.8, 30.7). Nineteen pts were tested for NECTIN4 amp, 6 of whom were positive (31.6%). Of these, 3 achieved a PR with an ORR of 50.0% (95% CI: 11.8, 88.2), and the remaining 3 had stable disease (SD; disease control rate 100.0%). All 3 NECTIN4 amp responders were previously treated with sacituzumab govitecan. Of the NECTIN4 non-amp pts, 1/13 had a PR: ORR of 7.7% (95% CI: 0.2, 36.0). Of note, the non-amp responder pt harbored a polysomy, with NECTIN4 and CEN1 copy number &gt;6 (NECTIN4:CEN1 ratio &lt;2.0). Four HR+ BC pts were tested for NECTIN4 amp. One responder (1/ 4) was also the only one harboring a NECTIN4 amp. Safety and tolerability of zele in the TNBC population was similar to a previously reported cohort of bladder cancer pts (Reig et al., 2024). Grade 3 or higher zele-related adverse events (AEs) occurred in 34.4% of all TNBC pts, and Grade 3 or higher zele-related serious adverse events (SAEs) occurred in 12.5% of all TNBC pts. Zele-related AE frequencies were similar in the NECTIN4 amp pts; however, no NECTIN4 amp pts had a zele-related SAE. Conclusions: NECTIN4 amplification appears to show predictive clinical utility in identifying pretreated TNBC pts with enhanced response to zelenectide pevedotin, with an ORR of 57.1% in NECTIN4 gene amp positive pts including polysomy versus an ORR of 13.3% in biomarker unselected TNBC. Despite the limited sample size, this post-hoc analysis underscores the promising anti-tumor activity of zelenectide pevedotin in pts with NECTIN4 amp TNBC, who continue to have significant unmet medical need for effective, well-tolerated therapy. These findings support further exploration of zele and NECTIN4 amp stratification strategies in BC pts, particularly TNBC. Citation Format: Niklas Klümper, Viktor Grünwald, Johannes Brägelmann, Meredith McKean, Elisa Fontana, Antoine Italiano, Loic Verlingue, Capucine Baldini, Valentina Boni, Alberto J Montero, Thibault de la Motte, Bernard Doger, Jordi Rodón Ahnert, Cecile Vicier, Carly Campbell, Tara Gelb, Sean Santos, Kate Josephs, Cong Xu, Nicholas Keen, Kevin Lee, Santiago Arroyo, Markus Eckstein. Enhanced anti-tumor activity of zelenectide pevedotin in triple negative breast cancer (TNBC) patients (pts) with NECTIN4 gene amplification (amp) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-21.

Base-Mediated Formal Denitrogenative Insertion of Nonactivated Triazoles into Aldehydes: Stereospecific Synthesis of Highly Substituted Acrylamides

2025-06-13

L. Teng , S. WANG , Zhu Wenxiang +5 more | Organic Letters

A base-mediated denitrogenative insertion of nonactivated N(1)-aryl-1,2,3-triazoles into aldehydes to construct trisubstituted (E)-acrylamides was developed. The reaction, which involves formal insertion of two atoms from the triazole into the aldehyde … A base-mediated denitrogenative insertion of nonactivated N(1)-aryl-1,2,3-triazoles into aldehydes to construct trisubstituted (E)-acrylamides was developed. The reaction, which involves formal insertion of two atoms from the triazole into the aldehyde C═O bond with concomitant loss of nitrogen, proceeds at ambient temperature with complete stereocontrol. This method provides a highly efficient and straightforward means to construct functionalized acrylamides by employing readily available 1,2,3-triazoles and aldehydes as starting materials.

Correction: Chavda et al. Peptide-Drug Conjugates: A New Hope for Cancer Management. Molecules 2022, 27, 7232

2025-06-13

Vivek P. Chavda , Hetvi K. Solanki , Majid Davidson +2 more | Molecules

In the original publication cited above [...] In the original publication cited above [...]

Controlled/″Living″ Click Polymerization with Possible Bidirectional Chain-Growth Propagation during Polyaddition

2025-06-13

Satoshi Sakai , Takuya Nakamura , Seiichiro Uchida +5 more | Journal of the American Chemical Society

In this work, we found a new class of controlled/″living″ polymerization system, which proceeds bidirectional fashion using click reaction of AB monomer bearing azide and alkyne functionalities in a single … In this work, we found a new class of controlled/″living″ polymerization system, which proceeds bidirectional fashion using click reaction of AB monomer bearing azide and alkyne functionalities in a single molecule. The click polymerization of the AB monomer proceeded well using both azide and alkyne initiators in a well-controlled manner in either growth direction to afford polymers with predetermined molecular weights and narrow molecular weight distributions, as well as the terminal structures inherited from the initiator. Especially, the polymerizations with the difunctional initiators provided well-defined linear polymers with azide or alkyne groups at both termini. This approach also allows for polymerization control over the second monomer to give a block copolymer.

Facile Synthesis of 5‐Halo‐1,2,3‐triazole‐fused Benzotricyclic Frameworks from 1‐(ω‐Azidoalkyl)‐2‐(2,2‐dihalovinyl)arenes and their Application in Fluorescent Triazole Derivatives

2025-06-13

Takeshi Hata , Seiya Kikukawa , M. Ebihara +7 more | European Journal of Organic Chemistry

By heating 1‐(ω‐azidoalkyl)‐2‐(2,2‐dihalovinyl)arenes in DMF, intramolecular Huisgen cycloaddition between the azido group and the 1,1‐dihalovinyl moiety proceeded smoothly to afford 5‐halo‐1,2,3‐triazole‐fused tricyclic benzocondensed compounds. Leveraging the remaining halogen groups, carbon‐chain … By heating 1‐(ω‐azidoalkyl)‐2‐(2,2‐dihalovinyl)arenes in DMF, intramolecular Huisgen cycloaddition between the azido group and the 1,1‐dihalovinyl moiety proceeded smoothly to afford 5‐halo‐1,2,3‐triazole‐fused tricyclic benzocondensed compounds. Leveraging the remaining halogen groups, carbon‐chain extension via Mizoroki–Heck or Suzuki–Miyaura coupling reactions, followed by an intramolecular Friedel–Crafts reaction, furnished polycyclic systems incorporating fused triazole rings. Furthermore, transformation of the halogen groups into 2‐nitrobenzene derivatives via Suzuki–Miyaura cross‐coupling, followed by a Cadogan reaction using triphenylphosphine, provided a series of fluorescent pentacyclic compounds.

Cu-Mediated Click Chemistry Approach: Synthesis, Characterization, and Anti-Mycobacterial Activity of 2-(4-((5-Bromo-3-formyl-1H-indol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide Derivatives

2025-06-12

Parth Manvar , Dharmesh Katariya , Amita Vyas +2 more | Reviews and Advances in Chemistry

Click on Click: Click-Flavone Glycosides Encapsulated in Click-Functionalised Polymersomes for Glioblastoma Therapy

2025-06-12

Nuno M. Saraiva , Ana Catarina Alves , Ana Isabel Barbosa +4 more | Pharmaceutics

In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and … In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and alkyne groups and therefore, the 3,7-dihydroxyflavone (1) was first converted in 3,7-(prop-2-yn-yloxy)flavone (2) and acetobromo-α-D-glucose (3) was converted into 2,3,4,6-tetra-O-acetyl-β-glucopyranosyl azide (4). Subsequently, a click reaction was performed via copper-catalysed cycloaddition (CuAAC) between 2 and 4, as well as between 2 and 2-acetamido-3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl (AG931) and, 2 and commercial 2-azidoethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl (AG358), resulting in three distinct disubstituted flavone glycosides (5a–5c). Biological assays performed on L929 fibroblast cell lines and human glioblastoma astrocytoma U-251 cell lines indicated cytocompatibility with fibroblasts and reduced metabolic activity of GBM cells in the presence of compound 5b and 5c. To enhance therapeutic effect, improve local drug delivery, and overcome solubility issues of these high molecular weight compounds, the synthesised compounds were encapsulated in polymeric particles (polymersomes, PMs) composed of polylactic acid-polyethylene glycol (PEG-PLA) functionalized, once more by click chemistry, with 0.1 mol% transferrin mimetic (T7—HRPYIAH) peptide. The PMs were prepared by solvent displacement and exhibited stability over 100 days, encapsulation efficiency of 39–93%, and mean size diameters of 120–180 nm. The toxicity assays of the PMs on the U-251 cell line showed a significant decrease in metabolic activity, supporting the potential of this delivery system against GBM. Among the PMs tested, the flavone 5c-based PM demonstrated the highest efficacy.