DOCSLIB.ORG

Bioconjugation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bioconjugation research highlights BIOCONJUGATION insensitive to ReACT, the probe was applied transcripts along with developmental to selectively label reactive methionines for delay and cell cycle progression defects, Methionine’s time to shine ­­activity-based protein profiling, leading to indicative of a defective MZT. Overall, these Science 355, 597–602 (2017) the identification of hyperreactive residues findings indicate that the m6A modification in enolase that have redox-active functions has a key role in transcriptome switching in vivo. With methionine now a viable choice during early embryo development. GM for chemoselective bioorthogonal tagging, the options for bioconjugation are wider IMAGING AAAS than ever. CD Luciferase matchmaker DEVELOPMENT J. Am. Chem. Soc. 139, 2351–2358 (2017) Methionine is one of the rarest amino Marking the transition Nature , 475–478 (2017) acids in proteins, making it a potentially 542 attractive handle for highly selective protein N6-Methyladenosine (m6A) is an mRNA modification. However, because of a lack post-translational modification that is of robust bioorthogonal reactions for recognized by the RNA-binding protein targeting methionine, it has historically YTHDF2, which regulates mRNA stability. JACS been overlooked in favor of the other In order to understand the dynamics of sulfur-containing residue, cysteine, which m6A modification during embryonic is more nucleophilic. Lin et al. have now development, Zhao et al. performed developed a modification strategy that m6A sequencing of zebrafish maternal utilizes methionine’s redox activity for transcripts and found that 36% were conjugation under physiological conditions. m6A modified. Given that these maternal Bioluminescence imaging techniques This method, redox-activated chemical transcripts decreased in abundance during use luciferase to catalyze the oxidation tagging (ReACT), relies on an oxaziridine the maternal–zygotic transition (MZT), of a luciferin substrate, producing light. reagent that converts the methionine side with a corresponding increase in zygotic While natural and artificial variants of chain to a sulfimide conjugation product transcription, the authors hypothesized that both enzyme and substrate enable imaging while reducing the reagent to an aldehyde. YTHDF2 might be involved in maternal with different wavelengths of light, the This reaction is selective for methionine mRNA clearance. Injection of GFP- poor selectivity of luciferases for their over other nucleophilic amino acids labeled mRNA with and without the m6A cognate luciferins (over other structurally and does not denature proteins, and the modification into maternal ythdf2 zebrafish similar luciferins) hampers their use in product is stable when exposed to reducing mutants revealed that m6A-modified RNA multicomponent imaging. To address this reagents or elevated temperatures for up exhibited a slower rate of degradation shortcoming, Jones et al. targeted both sides to one hour. To demonstrate its utility, during the MZT in these mutants relative of the luciferase–luciferin pair to engineer the authors applied the ReACT method to wild-type embryos. Consistent with this orthogonality. First, the authors designed to label proteins with alkyne- or azide- result, maternal ythdf2 zebrafish mutants and synthesized a panel of luciferin analogs containing tags for further click chemistry exhibited an upregulation of maternal with increased steric bulk that weakened and to synthesize antibody–drug conjugates. transcripts involved in cell cycle and their binding to the wild-type luciferase Furthermore, as methionine sulfoxide is reproduction and lowered levels of zygotic while retaining their intrinsic potential for light emission. The authors then generated libraries of luciferase variants by targeted DRUG DISCOVERY mutagenesis at residues predicted to be PLoS Pathog. doi:10.1371/ important for substrate binding. Screening Uncoupling coupled transport journal.ppat.1006180 (2017) this mutant library for enzymes that were active with luciferin analogs also enabled The human malaria parasite Plasmodium falciparum has developed resistance to most iterative rounds of library diversification, and a secondary screen rated all of the © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2017 existing drugs, so drugs with new mechanisms of action are urgently needed. One parasite pathway that is underexplored as a potential therapeutic target is that involved pairwise combinations of enzyme and in the generation of ATP. The parasite takes up glucose and converts it via glycolysis substrate for orthogonality. From these to lactate, generating ATP in the process. The lactate end product is exported from the screens, three luciferases were identified parasite via a proton-coupled (pH-dependent) transporter. Hapuarachchi et al. screened that were capable of orthogonal activation a curated collection of antiplasmodial compounds for their effect on parasite pH and by select luciferin analogs in vitro and in identified 15 compounds that acidified the parasite. Monitoring the acidification under cell culture. These new luciferase–luciferin conditions in which glycolysis was either active or turned off revealed that 2 of the 15 pairs are themselves potentially useful hits exerted their effect on pH through the inhibition of proton-coupled lactate efflux. contributions to the bioluminescence Parasites selected for resistance to one of these two compounds that were also resistant toolbox, and this approach to their to the otheR had a mutation in the lactate–H+ transporter PfFNT. The compounds generation could be applied to future efforts inhibited lactate transport both in isolated parasites and in Xenopus oocytes expressing in developing selective imaging probes. CD the PfFNT transporter. The resistance-associated mutation in PfFNT reduced inhibition of transport in both systems. This study highlights the potential of the lactate transporter PfFNT as an antimalarial drug target. MB Written by Mirella Bucci, Caitlin Deane and Grant Miura NATURE CHEMICAL BIOLOGY | VOL 13 | APRIL 2017 | www.nature.com/naturechemicalbiology 343.
Load more

Recommended publications
  • Development and Applications of N-Terminal Protein Bioconjugation Reactions
    Development and Applications of N-terminal Protein Bioconjugation Reactions by Kanwal Siddique Palla A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Matthew B. Francis, Chair Professor Jamie Cate Professor Wenjun Zhang Summer 2016 Development and Applications of N-terminal Protein Bioconjugation Reactions Copyright © 2016 By: Kanwal Siddique Palla Abstract Development and Applications of N-terminal Protein Bioconjugation Reactions by Kanwal Siddique Palla Doctor of Philosophy in Chemistry University of California, Berkeley Professor Matthew B. Francis, Chair With highly evolved structures and function, proteins have an extraordinarily diverse range of capabilities. In order to take advantage of their unparalleled specificity in the field of chemical biology, bioconjugation methods can be used to produce synthetically modified proteins. As ap- plications for protein-based materials are becoming ever-increasingly complex, there is a constant need for methodologies that can covalently modify protein substrates. More specifically, there is a requirement for reliable and chemoselective reactions that result in well-defined bioconjugates that are modified in a single location. We have developed a protein transamination strategy that uses N-methylpyridinium-4-carboxaldehyde benzenesulfonate salt (Rapoport's salt) to oxidize the N-terminal amine to a ketone or aldehyde functionality. We have identified high-yielding con- ditions for this reaction, such as N-terminal sequence and pH, and shown its applicability in the modification of several protein systems. In addition, we have used N-terminal protein modifica- tion methodologies in the synthesis of protein-DNA conjugates, towards the goal of developing a generalizable DNA-directed protein immobilization platform.
    [Show full text]
  • 'Photochemical Reactions in the Synthesis of Protein–Drug Conjugates'
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 Photochemical Reactions in the Synthesis of Protein–Drug Conjugates Holland, Jason P ; Gut, Melanie ; Klingler, Simon ; Fay, Rachael ; Guillou, Amaury Abstract: The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre‐association (non‐covalent ligand‐protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed. DOI: https://doi.org/10.1002/chem.201904059 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-183515 Journal Article Accepted Version Originally published at: Holland, Jason P; Gut, Melanie; Klingler, Simon; Fay, Rachael; Guillou, Amaury (2020). Photochemical Reactions in the Synthesis of Protein–Drug Conjugates. Chemistry - A European Journal, 26(1):33-48. DOI: https://doi.org/10.1002/chem.201904059 Photochemical reactions in the synthesis of protein-drug conjugates Jason P.
    [Show full text]
  • Chemical Tools for Residue-Specific and Secondary Amine Selective Petasis (SASP) Bioconjugation of Peptides and Proteins
    Seton Hall University eRepository @ Seton Hall Seton Hall University Dissertations and Theses (ETDs) Seton Hall University Dissertations and Theses Spring 5-4-2020 Chemical tools for Residue-Specific and Secondary Amine Selective Petasis (SASP) bioconjugation of Peptides and Proteins Yonnette Sim [email protected] Follow this and additional works at: https://scholarship.shu.edu/dissertations Part of the Biochemistry Commons Recommended Citation Sim, Yonnette, "Chemical tools for Residue-Specific and Secondary Amine Selective Petasis (SASP) bioconjugation of Peptides and Proteins" (2020). Seton Hall University Dissertations and Theses (ETDs). 2776. https://scholarship.shu.edu/dissertations/2776 Chemical tools for Residue-Specific and Secondary Amine Selective Petasis (SASP) bioconjugation of Peptides and Proteins A dissertation submitted to Seton Hall University in partial fulfillment for the Doctor of Philosophy Degree By: Yonnette E. Sim May 2020 Department of Chemistry and Biochemistry Seton Hall University South Orange, NJ. 07079 USA © 2020 Yonnette E. Sim DocuSign Envelope ID: 9EF6018D-72DB-4316-B86E-3A103260E910 We certify that we have read this dissertation and in our opinion it is adequate in scientific scope and quality as dissertation for the degree of Doctor of Philosophy Dr. Gregory R. Wiedman Mentor Dr. Monika Raj Co-Mentor (No Longer SHU Faculty) Dr. Joseph Badillo Member of Dissertation Committee Dr. Stephen Kelty Department Chair Seton Hall University I dedicate this thesis to my husband, Ebo, my children Ebony and Ethan for their tremendous love and support & My late parents Rupert and Theresa for their love and wisdom. “The only limit to the height of your achievements is the reach of your dreams and your willingness to work for them” – Michelle Obama i ACKNOWLEDGEMENTS First I would like to express my appreciation and thanks to my research mentor, Dr.
    [Show full text]
  • The Impact of Emerging Bioconjugation Chemistries on Radiopharmaceuticals
    FOCUS ON MOLECULAR IMAGING The Impact of Emerging Bioconjugation Chemistries on Radiopharmaceuticals Rachael Fay and Jason P. Holland Department of Chemistry, University of Zurich, Zurich, Switzerland also led to pronounced differences the uptake, retention, and ex- The use of radiolabeled antibodies, immunoglobulin fragments, and cretion of these three radiotracers in mice bearing LNCaP tumors. other proteins are an increasingly important sector of research for For radiotracers based on antibodies, and other proteins, less is diagnostic imaging and targeted radiotherapy in nuclear medicine. known about the impact that linker methodology may have on the As with all radiopharmaceuticals, efficient radiochemistry is a pre- stability, pharmacokinetics, and target specificity of the ensuing requisite to clinical translation. For proteins, variations in the primary radiotracer. Until recently, our collective experience with radiola- amino acid sequence, the secondary structures, and tertiary folds, beled antibodies has relied on a small handful of conjugation as well as differences in the size, charge, polarity, lipophilicity, and routes. Classic chemistries typically involve reactions of native the presence of posttranslational modifications, add complexity to the system. The choice of radionuclide or chelate, and its impact on cysteine or lysine residues (4–11). For example, thiolate groups of the thermodynamic, kinetic, and metabolic stability of a radiotracer, cysteine side chains readily undergo Michael addition reactions e has attracted much attention but the chemistry by which the radio- with maleimide groups, and the -NH2 group of lysine side chains nuclide is conjugated to the protein scaffold is of equal importance. participates in nucleophilic reactions using activated esters or iso- Recently, a wealth of creative advances in protein ligation methods thiocyanates.
    [Show full text]
  • Antibody Conjugates: from Heterogeneous Populations to Defined Reagents
    Antibodies 2015, 4, 197-224; doi:10.3390/antib4030197 OPEN ACCESS antibodies ISSN 2073-4468 www.mdpi.com/journal/antibodies Review Antibody Conjugates: From Heterogeneous Populations to Defined Reagents Patrick Dennler 1, Eliane Fischer 1 and Roger Schibli 1,2,* 1 Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland; E-Mails: [email protected] (P.D.); [email protected] (E.F.) 2 Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +41-56-310-2837. Academic Editor: Dimiter S. Dimitrov Received: 13 June 2015 / Accepted: 14 July 2015 / Published: 3 August 2015 Abstract: Monoclonal antibodies (mAbs) and their derivatives are currently the fastest growing class of therapeutics. Even if naked antibodies have proven their value as successful biopharmaceuticals, they suffer from some limitations. To overcome suboptimal therapeutic efficacy, immunoglobulins are conjugated with toxic payloads to form antibody drug conjugates (ADCs) and with chelating systems bearing therapeutic radioisotopes to form radioimmunoconjugates (RICs). Besides their therapeutic applications, antibody conjugates are also extensively used for many in vitro assays. A broad variety of methods to functionalize antibodies with various payloads are currently available. The decision as to which conjugation method to use strongly depends on the final purpose of the antibody conjugate. Classical conjugation via amino acid residues is still the most common method to produce antibody conjugates and is suitable for most in vitro applications. In recent years, however, it has become evident that antibody conjugates, which are generated via site-specific conjugation techniques, possess distinct advantages with regard to in vivo properties.
    [Show full text]
  • Research Summary Reversible and Irreversible Chemoselective Bioconjugation
    Research Summary Reversible and Irreversible Chemoselective Bioconjugation - I have been involved in developing ground-breaking new methodologies, with the Baker and Caddick research groups, that allow for reversible and irreversible homogeneous protein modification.1-8 For example, dihalomaleimides and dihalopyridazinediones can be used for the reversible, or irreversible, conjugation of biomolecules in high yield on various proteins.1,2,4,7,8 Reversible constructs have been shown to disassemble in the reducing-environment of the cytoplasm of mammalian cells.2 The methodology is currently being exploited in a variety of applications such as the homogeneous modification of antibodies and antibody fragments (see above),8 and in reversible-affinity labelling for pull-down experiments. Aerobic Hydroacylation - In recent years, I have been involved in the development of a fundamentally novel approach to radical C-H bond activation that has been published in high impact journals such as Nature Chemistry.9,10 This work is based on the discovery that acyl radicals generated from aldehydes in the presence of air can undergo hydroacylation with certain alkenes (see right). To date, the hydroacylation of vinyl sulfonates, vinyl sulfones, unsaturated esters and vinyl phosphonates has been reported, to generate a variety of unsymmetrical ketones.10 I have also explored the aerobic hydroacylation of azo-dicarboxylates with various aldehydes to generate hydrazide dicarboxylates in high yields, even when employing aldehyde as the limiting reagent.11
    [Show full text]
  • Development of Bioorthogonal Reactions and Their Applications in Bioconjugation
    Molecules 2015, 20, 3190-3205; doi:10.3390/molecules20023190 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Development of Bioorthogonal Reactions and Their Applications in Bioconjugation Mengmeng Zheng, Li Zheng, Peiyuan Zhang, Jinbo Li * and Yan Zhang * Institute of Chemistry & BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China; E-Mails: [email protected] (M.Z.); [email protected] (L.Z.); [email protected] (P.Z.) * Authors to whom correspondence should be addressed; E-Mails: [email protected] (J.L.); [email protected] (Y.Z.); Tel.: +86-25-8968-1327 (J.L.); +86-25-8359-3072 (Y.Z.); Fax: +86-25-8368-5976 (J.L. & Y.Z.). Academic Editor: Scott Reed Received: 5 January 2015 / Accepted: 2 February 2015 / Published: 16 February 2015 Abstract: Biomolecule labeling using chemical probes with specific biological activities has played important roles for the elucidation of complicated biological processes. Selective bioconjugation strategies are highly-demanded in the construction of various small-molecule probes to explore complex biological systems. Bioorthogonal reactions that undergo fast and selective ligation under bio-compatible conditions have found diverse applications in the development of new bioconjugation strategies. The development of new bioorthogonal reactions in the past decade has been summarized with comments on their potentials as bioconjugation method in the construction of various biological probes for investigating their target biomolecules. For the applications of bioorthogonal reactions in the site-selective biomolecule conjugation, examples have been presented on the bioconjugation of protein, glycan, nucleic acids and lipids. Keywords: bioorthogonal reactions; bioconjugation strategies; biomolecules; chemical probes 1.
    [Show full text]
  • A Flow Platform for Degradation-Free Cuaac Bioconjugation
    ARTICLE DOI: 10.1038/s41467-018-06551-0 OPEN A flow platform for degradation-free CuAAC bioconjugation Marine Z.C. Hatit1, Linus F. Reichenbach1, John M. Tobin2, Filipe Vilela 2, Glenn A. Burley 1 & Allan J.B. Watson 3 The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is a cornerstone method for the ligation of biomolecules. However, undesired Cu-mediated oxidation and Cu- 1234567890():,; contamination in bioconjugates limits biomedical utility. Here, we report a generic CuAAC flow platform for the rapid, robust, and broad-spectrum formation of discrete triazole bio- conjugates. This process leverages an engineering problem to chemical advantage: solvent- mediated Cu pipe erosion generates ppm levels of Cu in situ under laminar flow conditions. This is sufficient to catalyze the CuAAC reaction of small molecule alkynes and azides, fluorophores, marketed drug molecules, peptides, DNA, and therapeutic oligonucleotides. This flow approach, not replicated in batch, operates at ambient temperature and pressure, requires short residence times, avoids oxidation of sensitive functional groups, and produces products with very low ppm Cu contamination. 1 Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK. 2 Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, UK. 3 School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK. Correspondence and requests for materials should be addressed to G.A.B. (email: [email protected]) or to A.J.B.W. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:4021 | DOI: 10.1038/s41467-018-06551-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06551-0 he Cu-catalyzed azide-alkyne cycloaddition (CuAAC) of a copper tube with the formation of a highly active CuAAC reaction (Scheme 1a) is a method of widespread utility catalyst under laminar flow conditions.
    [Show full text]
  • The Impact of Emerging Bioconjugation Chemistries on Radiopharmaceuticals
    Journal of Nuclear Medicine, published on March 22, 2019 as doi:10.2967/jnumed.118.220806 The impact of emerging bioconjugation chemistries on radiopharmaceuticals Rachael Fay and Jason P. Holland* University of Zurich, Department of Chemistry, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland * Corresponding Author: Prof. Dr Jason P. Holland Tel: +41.44.63.53.990 ORCID: 0000-0002-0066-219X E-mail: [email protected] Website: www.hollandlab.org First author: Rachael Fay E-mail: [email protected] Running Title: Bioconjugation methods in radiosynthesis Words (Main text): 4048 incl. 48 references Page 1 ABSTRACT The use of radiolabeled antibodies, immunoglobulin fragments and other proteins are an increasingly important sector of research for diagnostic imaging and targeted radiotherapy in Nuclear Medicine. As with all radiopharmaceuticals, efficient radiochemistry is a prerequisite to clinical translation. For proteins, variations in the primary amino acid sequence, the secondary structures and tertiary folds, as well as differences in size, charge, polarity, lipophilicity, and the presence of post-translational modifications, add complexity to the system. The choice of radionuclide or chelate, and their impact on the thermodynamic, kinetic and metabolic stability of a radiotracer has attracted much attention but the chemistry by which the radionuclide is conjugated to the protein scaffold is of equal importance. Recently, a wealth of creative advances in protein ligation methods based on chemical, photochemical and enzyme-mediated processes have emerged. As radiochemists explore alternative bioconjugation strategies, this article considers their potential impact on radiotracer design. Keywords: Bioconjugation, immuno-PET, antibodies, protein ligation, enzymes, photoradiochemistry Page 2 INTRODUCTION It has long been established that the precise nature of the chemical linker used to couple a small- molecule or peptide to a radiometal complex can have a profound impact on the properties of a radiotracer (1).
    [Show full text]
  • Bioconjugation Reagents
    Bioconjugation Reagents Bioconjugation is the formation of complexes by chemically bonding for Thiol Group functional molecules to biomolecules such as DNA, RNA, proteins, lipids O and sugars under mild conditions. The bioconjugated complexes are used R = NH(CH2)2S S R = HN(CH2)6NH C (CH2)2S S to develop new methods, for example in drug discovery, ligand binding N N assays, disease diagnosis, and high-throughput screening. There have 10mg / 50mg [P2471] New 25mg / 100mg [B5749] been many recent reports of the chemical modification of biomolecules O O with non-natural bioorthogonal functional groups such as azide. O O NH(C H O) (CH ) NH C (CH ) N R = NH(C2H4O)2(CH2)2NH C (CH2)2 N R = 2 4 6 2 2 2 2 10mg / 50mg [B5563] 50mg [B3174] O O Biotinylation Reagents for Aldehyde or Carbonyl Group The avidin-biotin system is widely used for bioanalysis and bioassays including flow cytometry, ELISA, O immunohistochemical staining, western blotting and others. Biotin labeling (biotinylation) is also NH(CH ) C NHNH commonly used for conjugating proteins, especially antibodies, and other various molecules. R = NHNH2 R = 2 5 2 Biotinylation is one of the most essential methods in the field of immunoassay where antigens are 25mg / 100mg [B2431] 25mg / 100mg [H1071] detected using antibodies. Streptavidin is a protein from the avidin family having extraordinarily high affinity for biotin, in fact, the interaction of biotin with streptavidin is among the strongest non-covalent O O affinities known in nature. In order to detect the biotinylated substance, modification of streptavidin with R = NH(C2H4O)2(CH2)2 C NHNH2 R = NH(C2H4O)4(CH2)2 C NHNH2 fluorescent label or enzyme is required.
    [Show full text]
  • Organic Catalysts in the 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides
    HETEROCYCLES, Vol. , No. , , pp. -. © The Japan Institute of Heterocyclic Chemistry Received, ,Accepted, , Published online, . DOI: 10.3987/COM- (Please do not delete.) MINI-REVIEW: ORGANIC CATALYSTS IN THE 1,3-DIPOLAR CYCLOADDITION REACTIONS OF NITRILE OXIDES Silvia Roscales* and Joaquín Plumet* Complutense University. Faculty of Chemistry.Organic Chemistry Department. Ciudad Universitaria, 28040, Madrid, Spain. Heterocycles, en prensa. DOI, 10.3987/REV-18-SR(F)4. Aparecerá en el Vol. 99, 2019. Abstract – In 1961, Huisgen categorized the nitrile oxides (NOs) as a member of a broader class of 1,3-dipoles that were capable of undergoing 1,3-dipolar cycloaddition (DC) reactions. Nevertheless, the cycloaddition (CA) reactions of NOs to alkenes and alkynes are in many cases hampered by the tendency to the dimerization of the NO to the related furoxan (1,2,5-oxadiazole-2-oxide). In addition, although monosubstituted alkenes and alkynes show high regioselectivity in their cycloadditions with NOs, 1,2-disubstituted derivatives often give mixtures of regioisomers. Catalyzed NOs cycloadditions constitute in many cases an appropriate response to these problems and, in particular, the metal catalyzed cycloaddition reactions have been extensively used. However, the cost, toxicity and removal of trace amounts of the metal residues from desired products is quite costly and challenging, while crucial, especially in the pharmaceutical industry. Obviously, alternative pathways under metal-free conditions to fulfill the metal-catalyzed reactions are highly appealing. The present review is devoted to the consideration of the use of organic molecules as catalysts for 1,3-dipolar cycloaddition reactions of nitrile oxides. CONTENTS 1. Introduction and objectives 1.1.
    [Show full text]
  • Copper-Catalyzed Azide Alkyne Cycloaddition Polymer Networks
    COPPER-CATALYZED AZIDE ALKYNE CYCLOADDITION POLYMER NETWORKS by Abeer Ahmed Alzahrani M.S., Chemistry, King Abdul-Aziz University, 2005 B.S. Chemistry, University of Umm Al-Qura University, 2000 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirement for the degree of Doctor of Philosophy, Department of Department of Chemistry and Biochemistry, 2014 This thesis entitled: Copper-Catalyzed Azide Alkyne Cycloaddition Polymer Networks written by Abeer Ahmed Alzahrani has been approved for the Department of Chemistry and Biochemistry ___________________________ Christopher N. Bowman, PhD. Date____________ ___________________________ Jeffrey W. Stansbury, PhD. Date____________ Committee members: Christopher N. Bowman, Jeffrey W. Stansbury Devatha P Nair, Daniel L. Feldheim, and Wei Zhang The final copy of this thesis has been examined by The signatories, and we find that both the content and the form meet acceptable presentation standards of scholarly work in the above mentioned discipline. COPPER-CATALYZED AZIDE ALKYNE CYCLOADDITION POLYMER NETWORKS Alzahrani, Abeer Ahmed, Ph.D., Dept. of Department of Chemistry and Biochemistry Thesis directed by Patten Professor, Christopher N. Bowman Abstract The click reaction concept, introduced in 2001, has since spurred the rapid development and reexamination of efficient, high yield reactions which proceed rapidly under mild conditions. Prior to the discovery of facile copper catalysis in 2002, the thermally activated azide- alkyne or Huisgen cycloaddition reaction was largely ignored following its discovery in large part due to its slow kinetics, requirement for elevated temperature and limited selectivity. Now, arguably, the most prolific and capable of the click reactions, the copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction is extremely efficient and affords exquisite control of the reaction.
    [Show full text]