DOCSLIB.ORG

Bioorthogonal Bioconjugation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bioorthogonal Bioconjugation Chemistry & Biology Review Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation Craig S. McKay1 and M.G. Finn1,* 1School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA *Correspondence: mgfi[email protected] http://dx.doi.org/10.1016/j.chembiol.2014.09.002 The selective chemical modification of biological molecules drives a good portion of modern drug develop- ment and fundamental biological research. While a few early examples of reactions that engage amine and thiol groups on proteins helped establish the value of such processes, the development of reactions that avoid most biological molecules so as to achieve selectivity in desired bond-forming events has revolution- ized the field. We provide an update on recent developments in bioorthogonal chemistry that highlights key advances in reaction rates, biocompatibility, and applications. While not exhaustive, we hope this summary allows the reader to appreciate the rich continuing development of good chemistry that operates in the bio- logical setting. Introduction: Bioorthogonal Click Chemistry oxygen and water (Kolb et al., 2001; Hawker and Wooley, Chemical biology involves the creation of nonbiological mole- 2005; Kolb and Sharpless, 2003; Wu et al., 2004). In vivo bio- cules that exert an effect on, or reveal new information about, orthogonal chemistry and click chemistry therefore overlap quite biological systems. Central to this field is the property of selec- a bit, reflecting the same underlying chemical principles applied tivity: ultimately, one wishes for molecules with perfectly selec- in somewhat different ways toward the discovery or develop- tive biological function, but in practice, one starts with as much ment of molecular function and information. chemical selectivity as possible and tests and refines from there. To meet stringent requirements of rate, selectivity, and Therefore, the ability to make chemical modifications that enable biocompatibility, the development of bioorthogonal reactions the direct detection of, or interaction with, biomolecules in their proceeds through several steps. First, of course, is the identifica- native cellular environments is at the heart of the chemical tion or invention of a highly specific ligation process that works biology enterprise. well in water. Potential problems associated with reactant/prod- Genetically encoded reporters, such as GFP and tetracysteine uct stabilities and reaction biocompatibility must be anticipated motifs, have been used to excellent effect for protein tagging, but and addressed. The reaction is first optimized ‘‘in the flask,’’ other molecules such as glycans, lipids, metabolites, and myriad where the fundamental scope, limitations, and mechanistic posttranslational modifications are not often amenable to this modifications are explored. Then the reaction is tested in a vari- type of labeling. Monoclonal antibodies usually provide sufficient ety of biological environments, escalating in complexity from target specificity, but are laborious to generate and are often un- aqueous media to biomolecule solutions to cultured cells. The able to enter cells and tissues. Covalent chemical modification most optimized transformations are then tested and employed has therefore emerged as an alternative strategy. Bioorthogonal in living organisms and animals (Sletten and Bertozzi, 2011b). reactant pairs, which are most suitable for such applications, are The reactions highlighted in the following section are at different molecular groups with the following properties: (1) they are mutu- stages of development toward the ultimate goal of in vivo appli- ally reactive but do not cross-react or interact in noticeable ways cation. Second-order rate constants for bioorthogonal reactions with biological functionalities or reactions in a cell, (2) they and reported to date span ten orders of magnitude, with the fastest their products are stable and nontoxic in physiological settings, labeling reactions reaching rates up to 105 MÀ1sÀ1. and (3) ideally, their reaction is highly specific and fast (Sletten This perspective provides a critical review of emerging bio- and Bertozzi, 2009). Rate is an often underappreciated factor conjugation strategies with comments on their general utility by the casual user of bioorthogonal chemical technology: very and challenges. We recommend several excellent published re- high rate constants are required for labeling cellular processes views for more comprehensive accounts of the underlying chem- that occur on fast time scales or with low abundance structures istries (Lang and Chin, 2014; Patterson et al., 2014; Prescher and in (or on) the cell. Bertozzi, 2005; Sletten and Bertozzi, 2009). We also provide a Bioorthogonal chemical reactions have emerged as highly few examples of emerging areas of applications such as trig- specific tools that can be used for investigating the dynamics gered release and prodrug activation. and function of biomolecules in living systems (Jewett and Ber- tozzi, 2010; Lang and Chin, 2014; Lim and Lin, 2010b; Patterson Bioorthogonal Conjugation Strategies and Applications et al., 2014; Prescher and Bertozzi, 2005; Sletten and Bertozzi, Typically, bioorthogonal reactions are exothermic by virtue 2009). Click chemistry, inspired by nature’s use of simple and of their highly energetic reactants or strongly stabilized pro- powerful connecting reactions, describes the most specific bio- ducts, and most involve the formation of carbon-heteroatom orthogonal reactions that are wide in scope, easy to perform, and (mostly N, O, and S) bonds. The reactions are typically fusion usually employ readily available reagents that are insensitive to processes that leave no byproducts or release nitrogen, or are Chemistry & Biology 21, September 18, 2014 ª2014 Elsevier Ltd All rights reserved 1075 Chemistry & Biology Review Figure 1. Strategies for Introducing and Conjugating Functionality to Biomolecule Targets (A) The two-step bioorthogonal labeling strategy: in the first step exogenous functionality is introduced genetically, metabolically or chemically, and the second step involves highly specific bioorthogonal reaction. (B) Site-specific bioconjugation based on native functionalities present in proteins. condensation processes that produce water as the only byprod- amino acid residues of peptides or proteins with high site selec- uct. Most applications involve a two-step approach that requires tivity has become important. The addressable functional groups introduction of bioorthogonal reporters by chemical, metabolic, can be introduced as unnatural amino acids (Wang et al., 2006), or genetic means, followed by modification of the biomolecule metabolic precursors, or installed by bioconjugation reactions. with the bioorthogonal labeling reaction (Figure 1). From a In the last category, the traditional processes, which usually pro- practical point of view, a bioorthogonal process finds useful ceed at low coupling rates or with poor chemoselectivity, have application if the reporter group is stable inside the cell and started to yield to new, highly selective organic transformation can be introduced by systemic distribution, metabolically, or and/or mechanistic modifications that improve ligation kinetics through a promiscuous enzymatic pathway (Sletten and Ber- and the stability of the resulting conjugates. tozzi, 2009). Most bioorthogonal reactions reported in the Emerging Approaches for Lysine Modifications. Lysine, argi- literature are chemoselective with respect to many, but not all, nine, histidine, and N-terminal amines contribute to proteins’ biological functionalities, and have been used to label protein positive charge at neutral pH and are often solvent exposed, in vitro or at the cell surface. Only a very few have been used making them amenable to chemical modification via acylation in much more complex systems inside living cells or animals: or alkylation (Table 1, entries 1–4). While primary amines readily the field, therefore, is really only just getting started. undergo reactions with activated esters, anhydrides, carbon- Site-Specific Bioconjugation Based on Native ates, isothiocyanates, and a range of other acylating and alkylat- Functionalities ing agents at slightly alkaline pH, these reactions are neither site Intrinsic bioconjugation reactions selectively target side chains specific nor protein specific. For example, N-hydroxysuccini- and termini of the 20 naturally occurring proteogenic amino acids mide (NHS) esters of a variety of types can cross-react with (Ban et al., 2013). Classical reactions such as thiol-maleimide the side-chain hydroxyl groups of tyrosine, serine, and threonine additions or amine-activated ester acylations are widely used if there is a nearby histidine to take up the NHS ester as an acyl for derivatizing proteins in vitro, but are typically not sufficiently imidazole, which in turn reacts with the –OH group resulting in an specific or rapid to modify a particular biomolecule in a higher ester bond (Hermanson, 2013). complexity cellular environment. Carbodiimide-based methods A variety of promising alternative approaches have recently for coupling of carboxylates are much less popular, probably appeared that take advantage of the special reactivity of aniline for reasons of positional selectivity or the potential for undesired groups, imine/iminium intermediates, and diazonium centers. protein crosslinking, although there are certainly exceptions Thus, a two-stage methodology from Francis and coworkers (Schlick
Load more

Recommended publications
  • 14.8 Organic Synthesis Using Alkynes
    14_BRCLoudon_pgs4-2.qxd 11/26/08 9:04 AM Page 666 666 CHAPTER 14 • THE CHEMISTRY OF ALKYNES The reaction of acetylenic anions with alkyl halides or sulfonates is important because it is another method of carbon–carbon bond formation. Let’s review the methods covered so far: 1. cyclopropane formation by the addition of carbenes to alkenes (Sec. 9.8) 2. reaction of Grignard reagents with ethylene oxide and lithium organocuprate reagents with epoxides (Sec. 11.4C) 3. reaction of acetylenic anions with alkyl halides or sulfonates (this section) PROBLEMS 14.18 Give the structures of the products in each of the following reactions. (a) ' _ CH3CC Na| CH3CH2 I 3 + L (b) ' _ butyl tosylate Ph C C Na| + L 3 H3O| (c) CH3C' C MgBr ethylene oxide (d) L '+ Br(CH2)5Br HC C_ Na|(excess) + 3 14.19 Explain why graduate student Choke Fumely, in attempting to synthesize 4,4-dimethyl-2- pentyne using the reaction of H3C C'C_ Na| with tert-butyl bromide, obtained none of the desired product. L 3 14.20 Propose a synthesis of 4,4-dimethyl-2-pentyne (the compound in Problem 14.19) from an alkyl halide and an alkyne. 14.21 Outline two different preparations of 2-pentyne that involve an alkyne and an alkyl halide. 14.22 Propose another pair of reactants that could be used to prepare 2-heptyne (the product in Eq. 14.28). 14.8 ORGANIC SYNTHESIS USING ALKYNES Let’s tie together what we’ve learned about alkyne reactions and organic synthesis. The solu- tion to Study Problem 14.2 requires all of the fundamental operations of organic synthesis: the formation of carbon–carbon bonds, the transformation of functional groups, and the establish- ment of stereochemistry (Sec.
    [Show full text]
  • Isonitrile-Responsive and Bioorthogonally Removable Tetrazine Protecting Groups
    UCLA UCLA Previously Published Works Title Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups. Permalink https://escholarship.org/uc/item/0hc9j0mv Journal Chemical science, 11(1) ISSN 2041-6520 Authors Tu, Julian Svatunek, Dennis Parvez, Saba et al. Publication Date 2020 DOI 10.1039/c9sc04649f Peer reviewed eScholarship.org Powered by the California Digital Library University of California Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups† Cite this: Chem. Sci., 2020, 11,169 a b c b All publication charges for this article Julian Tu, Dennis Svatunek, Saba Parvez, Hannah J. Eckvahl, have been paid for by the Royal Society Minghao Xu, ‡a Randall T. Peterson,c K. N. Houk b and Raphael M. Franzini *a of Chemistry In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si–C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity Creative Commons Attribution 3.0 Unported Licence.
    [Show full text]
  • S1 Supporting Information Copper-Catalyzed
    Supporting Information Copper-Catalyzed Semihydrogenation of Internal Alkynes with Molecular Hydrogen Takamichi Wakamatsu, Kazunori Nagao, Hirohisa Ohmiya*, and Masaya Sawamura* Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan Table of Contents Instrumentation and Chemicals S1 Characterization Data for Alkynes S1–S2 Procedure for the Copper-Catalyzed Semihydrogenation of Alkynes S2 Characterization Data for Alkenes S3–S5 References S5 NMR Spectra S6–S31 Instrumentation and Chemicals NMR spectra were recorded on a JEOL ECX-400, operating at 400 MHz for 1H NMR and 100.5 13 1 13 MHz for C NMR. Chemical shift values for H and C are referenced to Me4Si and the residual solvent resonances, respectively. Mass spectra were obtained with Thermo Fisher Scientific Exactive, JEOL JMS-T100LP or JEOL JMS-700TZ at the Instrumental Analysis Division, Equipment Management Center, Creative Research Institution, Hokkaido University. TLC analyses were performed on commercial glass plates bearing 0.25-mm layer of Merck Silica gel 60F254. Silica gel (Kanto Chemical Co., Silica gel 60 N, spherical, neutral) was used for column chromatography. Materials were obtained from commercial suppliers or prepared according to standard procedure unless otherwise noted. CuCl was purchased from Aldrich Chemical Co., stored under nitrogen, and used as it is. NatOBu, octane and 6-dodecyne 1a were purchased from TCI Chemical Co., stored under nitrogen, and used as it is. Diphenylacetylene 1j was purchased from Wako Chemical Co., stored under nitrogen, and used as it is. 1,4-Dioxane was purchased from Kanto Chemical Co., distilled from sodium/benzophenone and stored over 4Å molecular sieves under nitrogen.
    [Show full text]
  • The Synthesis of a Polydiacetylene to Create a Novel Sensory Material
    SELDE, KRISTEN A., M.S. The Synthesis of a Polydiacetylene to Create a Novel Sensory Material. (2007) Directed by Dr. Darrell Spells. 47pp. Sensory materials that respond to chemical and mechanical stimuli are under development in many laboratories. There are many significant uses of polydiacetylene compounds as sensory material. They have been applied to drug delivery, drug design, biomolecule development, cosmetics, and national security. In this study, experiments were carried out toward the development of a novel sensory material based on the established synthetic research on polydiacetylene compounds. Synthetic routes toward sensory materials with different head groups, different carbon chains lengths, and the incorporation of molecular imprints were explored. Diacetylene moieties, which can be used for polymer vesicle formation, were prepared by two main routes. In one route, 1-iodo-1-octyne and 1-iodo-1-dodecyne were prepared as starting materials for the synthesis of two diacetylene compounds (Diacetylene I and Diacetylene II). In the other route, a mesityl alkyne was used to prepare 5-iodo-1-pentyne, which was then used to prepare a triethylamino alkyne. This in turn was used to synthesize a diacetylene (Diacetylene III). Although each diacetylene product was formed, purification by column chromatography was found to be difficult. Experiments in vesicle formation, with and without molecular imprints, were also carried out using commercially available diacetylenes . THE SYNTHESIS OF A POLYDIACETYLENE TO CREATE A NOVEL SENSORY
    [Show full text]
  • Synthesis and Consecutive Reactions of Α-Azido Ketones: a Review
    Molecules 2015, 20, 14699-14745; doi:10.3390/molecules200814699 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Synthesis and Consecutive Reactions of α-Azido Ketones: A Review Sadia Faiz 1,†, Ameer Fawad Zahoor 1,*, Nasir Rasool 1,†, Muhammad Yousaf 1,†, Asim Mansha 1,†, Muhammad Zia-Ul-Haq 2,† and Hawa Z. E. Jaafar 3,* 1 Department of Chemistry, Government College University Faisalabad, Faisalabad-38000, Pakistan, E-Mails: [email protected] (S.F.); [email protected] (N.R.); [email protected] (M.Y.); [email protected] (A.M.) 2 Office of Research, Innovation and Commercialization, Lahore College for Women University, Lahore-54600, Pakistan; E-Mail: [email protected] 3 Department of Crop Science, Faculty of Agriculture, Universiti Putra Malaysia, Serdang-43400, Selangor, Malaysia † These authors contributed equally to this work. * Authors to whom correspondence should be addressed; E-Mails: [email protected] (A.F.Z.); [email protected] (H.Z.E.J.); Tel.: +92-333-6729186 (A.F.Z.); Fax: +92-41-9201032 (A.F.Z.). Academic Editors: Richard A. Bunce, Philippe Belmont and Wim Dehaen Received: 20 April 2015 / Accepted: 3 June 2015 / Published: 13 August 2015 Abstract: This review paper covers the major synthetic approaches attempted towards the synthesis of α-azido ketones, as well as the synthetic applications/consecutive reactions of α-azido ketones. Keywords: α-azido ketones; synthetic applications; heterocycles; click reactions; drugs; azides 1. Introduction α-Azido ketones are very versatile and valuable synthetic intermediates, known for their wide variety of applications, such as in amine, imine, oxazole, pyrazole, triazole, pyrimidine, pyrazine, and amide alkaloid formation, etc.
    [Show full text]
  • Topologically Designed Cylindrical and Spherical Building
    TOPOLOGICALLY DESIGNED CYLINDRICAL AND SPHERICAL BUILDING BLOCKS TO CONSTRUCT MODULAR-ASSEMBLED STRUCTURES IN GIANT SHAPE-AMPHPHILES A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Jing Jiang May 2018 TOPOLOGICALLY DESIGNED CYLINDRICAL AND SPHERICAL BUILDING BLOCKS TO CONSTRUCT MODULAR-ASSEMBLED STRUCTURES IN GIANT SHAPE-AMPHPHILES Jing Jiang Dissertation Approved: Accepted: Advisor Department Chair Dr. Stephen Z. D. Cheng Dr. Coleen Pugh Committee Chair Dean of the College Dr. Toshikazu Miyoshi Dr. Eric J. Amis Committee Member Dean of the Graduate School Dr. Tianbo Liu Dr. Chand K. Midha Committee Member Date Dr. Yu Zhu Committee Member Dr. Chrys Wesdemiotis ii ABSTRACT Giant shape amphiphiles with isobutyl polyhedral oligomeric silsesquioxane (BPOSS) cages as the periphery at two discotic trisubstituted derivative of benzene cores were specifically designed and synthesized. Depending upon the number of BPOSS cages, these molecules first assembled into either cylindrical or spherical units via π-π interactions among the core unites. The packing of the molecules is mandated by the steric hindrance of the BPOSS cages at the periphery with hydrogen bonding interactions. If the space-packing is allowed, the cylindrical building block can form. Otherwise, the cylindrical building block will be forced to interrupt periodically and to form spherical building blocks. These units can further modular assemble into supramolecular structures. The cylindrical units form columnar structures with both hexagonal and rectangular packing, while the spherical units construct a Frank-Kasper A15 phase, similar to the metal alloy structures. In addition, based on the mechanism proposed by this work, five more giant shape amphiphiles with high steric hindrance on the periphery were synthesized, these giant shape amphiphiles successfully formed A15 phases with precisely size control, iii validating the reliability of this strategy.
    [Show full text]
  • 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]
  • Staudinger Ligation: a Peptide from a Thioester and Azide
    ORGANIC LETTERS 2000 Staudinger Ligation: A Peptide from a Vol. 2, No. 13 Thioester and Azide 1939-1941 Bradley L. Nilsson,† Laura L. Kiessling,†,‡ and Ronald T. Raines*,†,‡ Departments of Chemistry and Biochemistry, UniVersity of Wisconsin-Madison, Madison, Wisconsin 53706 [email protected] Received May 4, 2000 ABSTRACT The technique of native chemical ligation enables the total chemical synthesis of proteins. This method is limited, however, by an absolute requirement for a cysteine residue at the ligation juncture. Here, this restriction is overcome with a new chemical ligation method in which a phosphinobenzenethiol is used to link a thioester and azide. The product is an amide with no residual atoms. New methods are facilitating the total chemical synthesis of residue in one peptide attacks the carbon of a C-terminal proteins.1 In particular, Kent and others have developed an thioester in another peptide to produce, ultimately, an amide elegant means to stitch together two unprotected peptides in bond between the two peptides (Scheme 1). Recently, Muir aqueous solution.2 In this method, which is called “native chemical ligation”, the thiolate of an N-terminal cysteine Scheme 1 † Department of Chemistry. ‡ Department of Biochemistry. (1) For historical references, see: (a) Merrifield, R. B. Science 1984, 232, 341-347. (b) Kent, S. B. Annu. ReV. Biochem. 1988, 57, 957-989. (c) Kaiser, E. T. Acc. Chem. Res. 1989, 22,47-54. (2) Dawson, P. E.; Muir, T. W.; Clark-Lewis, I.; Kent, S. B. Science 1994, 266, 776-779. For important precedents, see: (a) Wieland, T.; Bokelmann, E.; Bauer, L.; Lang, H.
    [Show full text]
  • Read the Book of Abstracts
    2o21 ONLINE May 10- 12 2021 International Symposium on SupraBiomolecular Systems 2021 Table of Contents TBD 1 Prof. Andreas Herrmann TBD 2 Prof. Rachel O’Reilly Tackling challenges in nanomedicine with responsive supramolecular polymers and advanced mi- croscopy 3 Dr. Silvia Pujals, Mr. Edgar Fuentes, Dr. Lorenzo Albertazzi Water Soluble Nanotubular Architectures from Amphiphilic Dinucleobases 4 Dr. Fatima Aparicio, Ms. Paula Blue Chamorro, Dr. Raquel Chamorro, Prof. David Gonzalez-Rodriguez Glyconucleolipids as new drug delivery systems for Parkinson’s disease treatment 5 Mr. Anthony Cunha, Dr. Alexandra Gaubert, Prof. Philippe Barthélémy, Dr. Benjamin Dehay, Dr. Laurent Latxague Membraneless compartments based on intrinsically disordered proteins: from biology towards new pro- tein materials 6 Prof. Paolo Arosio Low Molecular Weight Oleogel formation via unique keto-enol-type nucleolipid supramolecular assembly 8 Mr. Arthur KLUFTS-EDEL, Ms. Bérangère Dessane, Dr. Aladin Hamoud, Dr. Geoffrey Prévot, Dr. Antoine Lo- quet, Dr. Brice Kauffmann, Prof. Philippe Barthélémy, Prof. Sylvie Crauste-Manciet, Dr. Valérie Desvergnes Multi-responsive supramolecular fibers from peptide-based amphiphiles 9 Mr. Edgar Fuentes, Dr. Marieke Gerth, Dr. Jose Augusto Berrocal, Dr. Carlo Matera, Prof. Pau Gorostiza, Prof. Ilja Voets, Dr. Silvia Pujals, Dr. Lorenzo Albertazzi Electrostatic Protein Assemblies Towards Biohybrid Photoactive Materials 10 Dr. Eduardo Anaya-Plaza, Prof. Mauri Kostiainen Exploring Polyoxometalates as Non-destructive Staining Agents for Contrast-Enhanced Microfocus Com- puted Tomography of Biological Tissues 11 Ms. Sarah Vangrunderbeeck, Mr. Sébastien De Bournonville, Mrs. Hong Giang T. Ly, Prof. Wim De Borggraeve, Prof. Tatjana Parac-Vogt, Prof. Greet Kerckhofs Hydrogels with Photo-Switchable Stiffness: A Tool to Mimic Extra Cellular Matrix 13 Prof.
    [Show full text]
  • Durham E-Theses
    Durham E-Theses Some studies of polyuorinated polycyclic polyenes Hughes, Roger R. How to cite: Hughes, Roger R. (1975) Some studies of polyuorinated polycyclic polyenes, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/8213/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk SOME STUDIES OF POLYFLUORINATED POLYCYCLIC POLYENES by Roger R. Hughes, B.Sc. (Van Mildert College) The copyright of this thesis rests with the author. No quotation from it should be published without his prior written consent and information derived from it should be acknowledged. A thesis submitted to the University of Durham for the Degree of Doctor of Philosophy 1975 ABSTRACT The attempted addition of difluorocarbene, which was generated from hexafluoropropene epoxide, to polyfluorinated cyclic olefins was largely unsuccessful, although perfluorobicyclo[4,l,0]hept-3-ene was isolated from the addition to perfluorocyclohexa-1,4-diene.
    [Show full text]
  • Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides
    Top Curr Chem (Z) (2016) 374:16 DOI 10.1007/s41061-016-0016-4 REVIEW Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides 1 1 Jan Dommerholt • Floris P. J. T. Rutjes • Floris L. van Delft2 Received: 24 November 2015 / Accepted: 17 February 2016 / Published online: 22 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract A nearly forgotten reaction discovered more than 60 years ago—the cycloaddition of a cyclic alkyne and an organic azide, leading to an aromatic triazole—enjoys a remarkable popularity. Originally discovered out of pure chemical curiosity, and dusted off early this century as an efficient and clean bio- conjugation tool, the usefulness of cyclooctyne–azide cycloaddition is now adopted in a wide range of fields of chemical science and beyond. Its ease of operation, broad solvent compatibility, 100 % atom efficiency, and the high stability of the resulting triazole product, just to name a few aspects, have catapulted this so-called strain-promoted azide–alkyne cycloaddition (SPAAC) right into the top-shelf of the toolbox of chemical biologists, material scientists, biotechnologists, medicinal chemists, and more. In this chapter, a brief historic overview of cycloalkynes is provided first, along with the main synthetic strategies to prepare cycloalkynes and their chemical reactivities. Core aspects of the strain-promoted reaction of cycloalkynes with azides are covered, as well as tools to achieve further reaction acceleration by means of modulation of cycloalkyne structure, nature of azide, and choice of solvent. Keywords Strain-promoted cycloaddition Á Cyclooctyne Á BCN Á DIBAC Á Azide This article is part of the Topical Collection ‘‘Cycloadditions in Bioorthogonal Chemistry’’; edited by Milan Vrabel, Thomas Carell & Floris P.
    [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]