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Chemical Reviews Jun 2021Click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on... (Review)
Review
Click chemistry is an immensely powerful technique for the fast and efficient covalent conjugation of molecular entities. Its broad scope has positively impacted on multiple scientific disciplines, and its implementation within the nucleic acid field has enabled researchers to generate a wide variety of tools with application in biology, biochemistry, and biotechnology. Azide-alkyne cycloadditions (AAC) are still the leading technology among click reactions due to the facile modification and incorporation of azide and alkyne groups within biological scaffolds. Application of AAC chemistry to nucleic acids allows labeling, ligation, and cyclization of oligonucleotides efficiently and cost-effectively relative to previously used chemical and enzymatic techniques. In this review, we provide a guide to inexperienced and knowledgeable researchers approaching the field of click chemistry with nucleic acids. We discuss in detail the chemistry, the available modified-nucleosides, and applications of AAC reactions in nucleic acid chemistry and provide a critical view of the advantages, limitations, and open-questions within the field.
Topics: Alkynes; Azides; Click Chemistry; Cycloaddition Reaction; Nucleic Acids; Thermodynamics
PubMed: 33443411
DOI: 10.1021/acs.chemrev.0c00928 -
Chemical Society Reviews Oct 2022Click chemistry was extensively used to decorate synthetic multivalent scaffolds with glycans to mimic the cell surface glycocalyx and to develop applications in... (Review)
Review
Click chemistry was extensively used to decorate synthetic multivalent scaffolds with glycans to mimic the cell surface glycocalyx and to develop applications in glycosciences. Conjugation methods such as oxime ligation, copper(I)-catalyzed alkyne-azide cycloaddition, thiol-ene coupling, squaramide coupling or Lansbury aspartylation proved particularly suitable to achieve this purpose. This review summarizes the synthetic strategies that can be used either in a stepwise manner or in an orthogonal one-pot approach, to conjugate multiple copies of identical or different glycans to cyclopeptide scaffolds (namely multivalent glycocyclopeptides) having different size, valency, geometry and molecular composition. The second part of this review will describe the potential of these structures to interact with various carbohydrate binding proteins or to stimulate immunity against tumor cells.
Topics: Alkynes; Azides; Click Chemistry; Copper; Oximes; Peptides, Cyclic; Polysaccharides; Sulfhydryl Compounds
PubMed: 36193815
DOI: 10.1039/d2cs00640e -
Molecules (Basel, Switzerland) Oct 2022CuAAC (Cu catalyzed azide-alkyne cycloaddition) click-reaction is a simple and powerful method for the post-synthetic modification of organometallic complexes of...
CuAAC (Cu catalyzed azide-alkyne cycloaddition) click-reaction is a simple and powerful method for the post-synthetic modification of organometallic complexes of transition metals. This approach allows the selective introduction of additional donor sites or functional groups to the periphery of the ligand environment. This is especially important if a metalloligand with free donor sites, which are of the same nature as the primary site for the coordination of the primary metal, has to be created. The concept of post-synthetic modification of organometallic complexes by click-reaction is relatively recent and the currently available experimental material does not yet allow us to identify trends and formulate recommendations to address specific problems. In the present study, we have applied the CuAAC reaction for the post-synthetic modification of diimine mononuclear complexes Re(I), Pt(II) and Ir(III) with C≡C bonds at the periphery of the ligand environment and demonstrated that click-chemistry is a powerful tool for the tunable chemical post-synthetic modification of coordination compounds.
Topics: Alkynes; Azides; Catalysis; Click Chemistry; Copper; Cycloaddition Reaction; Ligands
PubMed: 36235030
DOI: 10.3390/molecules27196494 -
Nature Communications Aug 2022Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological...
Macrocycles have fascinated scientists for over half a century due to their aesthetically appealing structures and broad utilities in chemical, material, and biological research. However, the efficient preparation of macrocycles remains an ongoing research challenge in organic synthesis because of the high entropic penalty involved in the ring-closing process. Herein we report a photocatalyzed thiol-yne click reaction to forge diverse sulfur-containing macrocycles (up to 35-membered ring) and linear C2-linked 1,2-(S-S/S-P/S-N) functionalized molecules, starting from the simplest alkyne, acetylene. Preliminary mechanistic experiments support a visible light-mediated radical-polar crossover dihydrothiolation process. This operationally straightforward reaction is also amenable to the synthesis of organometallic complexes, bis-sulfoxide ligand and a pleuromutilin antibiotic drug Tiamulin, which provides a practical route to synthesize highly valued compounds from the feedstock acetylene gas.
Topics: Acetylene; Alkynes; Click Chemistry; Sulfhydryl Compounds
PubMed: 36008444
DOI: 10.1038/s41467-022-32723-0 -
Nature Chemistry Aug 2021Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's...
Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's lipophilicity, but the role of the membrane's rich and uniform stereochemistry as a permeability determinant is largely ignored in empirical and computational measurements. Here, we describe a new approach to measuring permeation using continuously generated microfluidic droplet interface bilayers (DIBs, generated at a rate of 480 per minute) and benchmark this system by monitoring fluorescent dye DIB permeation over time. Enantioselective permeation of alkyne-labelled amino acids (Ala, Val, Phe, Pro) and dipeptides through a chiral phospholipid bilayer was demonstrated using DIB transport measurements; the biological L enantiomers permeated faster than the D enantiomers (from 1.2-fold to 6-fold for Ala to Pro). Enantioselective permeation both poses a potentially unanticipated criterion for drug design and offers a kinetic mechanism for the abiotic emergence of homochirality via chiral transfer between sugars, amino acids and lipids.
Topics: Alkynes; Amino Acids; Cholesterol; Fluorescent Dyes; Lipid Bilayers; Permeability; Phosphatidylcholines; Stereoisomerism
PubMed: 34112989
DOI: 10.1038/s41557-021-00708-z -
Bioorganic Chemistry Feb 2024Antibody-Drug Conjugates (ADC) are a new class of anticancer therapeutics with immense potential. They have been rapidly advancing in the last two decades. This fast... (Review)
Review
Antibody-Drug Conjugates (ADC) are a new class of anticancer therapeutics with immense potential. They have been rapidly advancing in the last two decades. This fast speed of development has become possible due to several new technologies and methods. One of them is Click Chemistry, an approach that was created only two decades ago, but already is actively utilized for bioconjugation, material science and drug discovery. In this review, we researched the impact of Click Chemistry reactions on the synthesis and development of ADCs. The information about the most frequently utilized reactions, such as Michael's addition, Copper-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC), Strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC), oxime bond formation, hydrazine-iso-Pictet-Spengler Ligation (HIPS), Diels-Alder reactions have been summarized. The implementation of thiol-maleimide Click Chemistry reaction in the synthesis of numerous FDA-approved Antibody-Drug Conjugates has been reported. The data amassed in the present review provides better understanding of the importance of Click Chemistry in the synthesis, development and improvement of the Antibody-Drug Conjugates and it will be helpful for further researches related to ADCs.
Topics: Click Chemistry; Azides; Alkynes; Cycloaddition Reaction; Copper; Maleimides; Sulfhydryl Compounds
PubMed: 37995642
DOI: 10.1016/j.bioorg.2023.106982 -
Journal of the American Chemical Society Aug 2022A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a...
A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a sequential fashion. Key transformations include two atroposelective Larock-based macrocyclizations, one of which proceeds with exquisite regioselectivity despite bearing an unprotected alkyne. The synthesis is designed with medicinal chemistry considerations in mind, appending key portions of the molecule at a late stage. Requisite unnatural amino acid building blocks are easily prepared in an enantiopure form using C-H activation and decarboxylative cross-coupling tactics.
Topics: Alkynes; Amino Acids; Cyclization; Phenylpropionates
PubMed: 35926121
DOI: 10.1021/jacs.2c05892 -
Journal of the American Chemical Society May 2022The hexadehydro-Diels-Alder (HDDA) reaction converts a 1,3-diyne bearing a tethered alkyne (the diynophile) into bicyclic benzyne intermediates upon thermal activation....
The hexadehydro-Diels-Alder (HDDA) reaction converts a 1,3-diyne bearing a tethered alkyne (the diynophile) into bicyclic benzyne intermediates upon thermal activation. With only a few exceptions, this unimolecular cycloisomerization requires, depending on the nature of the atoms connecting the diyne and diynophile, reaction temperatures of 80-130 °C to achieve a convenient half-life (, 1-10 h) for the reaction. In this report, we divulge a new variant of the HDDA process in which the tether contains a central, quaternized nitrogen atom. This construct significantly lowers the activation barrier for the HDDA cycloisomerization to the benzyne. Moreover, many of the ammonium ion-based, alkyne-containing substrates can be spontaneously assembled, cyclized to benzyne, and trapped in a single-vessel, ambient-temperature operation. DFT calculations provide insights into the origin of the enhanced rate of benzyne formation.
Topics: Alkynes; Ammonium Compounds; Cycloaddition Reaction; Diynes; Temperature
PubMed: 35442671
DOI: 10.1021/jacs.2c00877 -
Bioconjugate Chemistry Mar 2018Interrogating biological systems is often limited by access to biological probes. The emergence of "click chemistry" has revolutionized bioconjugate chemistry by... (Review)
Review
Interrogating biological systems is often limited by access to biological probes. The emergence of "click chemistry" has revolutionized bioconjugate chemistry by providing facile reaction conditions amenable to both biologic molecules and small molecule probes such as fluorophores, toxins, or therapeutics. One particularly popular version is the copper-catalyzed azide-alkyne cycloaddition (AAC) reaction, which has spawned new alternatives such as the strain-promoted azide-alkyne cycloaddition reaction, among others. This focused review highlights practical approaches to AAC reactions for the synthesis of peptide or protein bioconjugates and contrasts current challenges and limitations in light of recent advances in the field. The conical success of antibody drug conjugates has expanded the toolbox of linkers and payloads to facilitate practical applications of bioconjugation to create novel therapeutics and biologic probes. The AAC reaction in particular is poised to enable a large set of functionalized molecules as a combinatorial approach to high-throughput bioconjugate generation, screening, and honing of lead compounds.
Topics: Alkynes; Animals; Azides; Click Chemistry; Cycloaddition Reaction; Humans; Nucleic Acids; Peptides; Proteins
PubMed: 29287474
DOI: 10.1021/acs.bioconjchem.7b00633 -
Organic Letters Jun 2021Azoheteroarenes make up an emerging class of photoswitchable compounds with unique photophysical properties and advantages over traditional azobenzenes. Therefore,...
Azoheteroarenes make up an emerging class of photoswitchable compounds with unique photophysical properties and advantages over traditional azobenzenes. Therefore, methods for synthesizing azoheteroarenes are highly desirable. Here, we utilize azide-alkyne click chemistry to access arylazo-1,2,3-triazoles, a previously unexplored class of azoheteroarenes that exhibit high thermal stabilities and near-quantitative bidirectional photoconversion. Controlling the catalyst or 1,3-dipole grants access to both regioisomeric arylazotriazoles and arylazoisoxazoles, highlighting the versatility of our approach.
Topics: Alkynes; Azides; Azo Compounds; Catalysis; Click Chemistry; Molecular Structure; Triazoles
PubMed: 34019429
DOI: 10.1021/acs.orglett.1c01230