DOCSLIB.ORG

Chemoselective Chemical Ligations of Biological Relevance

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemoselective Chemical Ligations of Biological Relevance Chemoselective Chemical Ligations of Biological Relevance "Bioconjugate Techniques" 2nd Edition, Greg T. Hermanson, Academic Press, 2008. Hermanson says that a 3rd edition is underway. Some Recent Reviews • "Functionalizing Nanoparticles with Biological Molecules: Developing Chemistries that Facilitate Nanotechnology", Sapsford, K. E.; Algar, W. R.; Berti, L.; Gemmill, K. B.; Casey, B. J.; Oh, E.; Stewart, M. H.; Medintz, I. L. Chem Rev 2013, 113, 1904–2074. • "Through the Looking Glass – a New World of Proteins Enabled by Chemical Synthesis", Kent, S.; Sohma, Y.; Liu, S.; Bang, D.; Pentelute, B.; Mandal, K. J. Pept. Sci. 2012, 18, 428–436. • "From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions", (1)Sletten, E. M.; Bertozzi, C. R. Acc Chem Res 2011, 44, 666-676. • "Bioorthogonal Chemistry for Site-Specific Labeling and Surface Immobilization of Proteins", Chen, Y.-X.; Triola, G.; Waldmann, H. Acc Chem Res 2011, 44, 762–773.. • "Bioconjugation with Strained Alkenes and Alkynes ", Debets, M. F.; van Berkel, S. S.; Dommerholt, J.; Dirks, A. T. J.; Rutjes, F. P. J. T.; van Delft, F. L. Acc Chem Res 2011, 805-815. • "Staudinger Ligation as a Method for Bioconjugation", van Berkel, S. S.; van Eldijk, M. B.; van Hest, J. Angew Chem Int Ed Engl 2011, 50, 8806–8827.. • "Advances in Bioconjugation", Kalia, J.; Raines, R. T. Current Organic Chemistry 2010, 14, 138–147. • "Chemoselective Ligation Techniques. Modern Applications of Time-Honored Chemistry", Tiefenbrunn, T. K. T.; Dawson, P. E. P. Biopolymers 2010, 94, 95–106. • "Chemoselective Ligation and Modification Strategies for Peptides and Proteins", Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed 2008, 47, 10030–10074. • "New Methods for Protein Bioconjugation", Francis, M. B. In Chemical Biology; Schreiber, S. L.; Kapoor, T. M.; Wess, G., Eds. Wiley-VCH Verlag GmbH: Weinheim, Germany, 2007; Vol. 1–3, pp. 593–634. Why are We Interested? Carboxylic Acid Ketoconjugation at Neutral pH. Ketoconjugations of RCO2H From Small Molecules to Chemical Biology to Materials? Chemoselective Bioconjugation • The chemoselective coupling of one reactive functional group specifically with another reactive functional group without side reactions: – Between biomolecules and other biomolecules, surfaces, or particles – Often in aqueous solutions or biological buffers and in the presence of biological material (proteins, DNA, RNA, complex carbohydrates). – A pair of specifically "tuned" chemoselective reactants is built into the design of cross-linkers, labeling reagents, modified biomolecules, and surfaces/particles. • Requires the rapid and selective reaction of substrates • Reactants must be stable near neutral pH and in aqueous environments "Advances in Bioconjugation", Kalia, J.; Raines, R. T. Current Organic Chemistry 2010, 14, 138–147. Bioorthogonal Chemistry • Bioorthogonal reactions – a particular type of bioconjugation where one specific "abiotic" functional group reacts with another specific "abiotic" functional group without any potential for cross-reactivity with biomolecular functionality in vivo. • Bioorthogonal reactions can be used to selectively functionalize biomolecules in complex biological milieu. • Bioorthogonal reactions are performed: – Inside of cells (cytosol) – On the surface of cells – In complex cell lysates Obtaining total chemoselectivity and perfect "bioorthogonality" is an ideal that is seldom achieved. Some of the more recent chemoselective ligations, which possess varying degrees of bioorthogonality, will be discussed. "Chemistry in Living Systems", Prescher, J. A.; Bertozzi, C. R. Nature Chemical Biology 2005, 1, 13–21. "Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality", Sletten, E. M.; Bertozzi, C. R. Angew. Chem. Int. Ed 2009, 48, 6974–6998. Native and Non-Native Methods • Bioconjugation methods rely on a variety of specific functional group interactions to achieve selectivity. They include, but are not limited to: – Carbon-sulfur conjugates – Hydrazide-aldehyde and related -C=N- conjugates – Phenylboronic acid (PBA)-salicylhydroxamic acid (SHA) conjugates – 4+2 and 3+2 dipolar cycloadditions – Staudinger reaction between an azide and a phosphine • Native bioconjugation methods use naturally-occurring biological processes, such as the formation of a peptide bond between a C-terminal thiol ester and an N-terminal cysteine. • Many bioconjugation methods, including those based on non-covalent interactions, are described in "Bioconjugate Techniques" 2nd Edition, Greg T. Hermanson, Academic Press, 2008. Carbon—Sulfur Linkages Traditional protein conjugation chemistries have exploited the reactivity of surface-exposed nucleophilic amino acids, such as cysteine (SH) or lysine (NH2). As a result, these methods typically result in heterogeneous mixtures of products. Thiol linkages at Cys represent one of the oldest methods of bioconjugation. • Technique relies on cysteine residues, which are the second least common amino acid in natural proteins (represent 1.7% of AA residues in natural proteins) . • Therefore, somewhat selective bioconjugation using cysteine residues can sometimes be achieved. • Common ligating functional groups for thiols are A a-iodoamides (alkylation), B maleimides (conjugate addition), and C disulfides (disulfide exchange). Other non-selective linkages used for bioconjugation are based on the formation of C=N bonds from hydrazides and oximes reacting with aldehyde and ketone functional groups. See: Curr. Org. Chem. 2010, 14, 138; Bioconjugate Chem 2008, 19, 2543–2548. Boronic Acid-Salicylhydroxamate Pairs • Phenylboronic acids (PBA) react with salicylhydroxamic acids (SHA) to form stable complexes. • Complex formation occurs in aqueous buffers between pH 5 to 9, tolerates high salt concentration (up to 1.5 M), as well as the presence of water miscible solvents, detergents, protein denaturants, etc. • Phenyldiboronic acids react with molecules or surfaces possessing at least two near-neighbor salicylhydroxamic acids to form highly stable bis-conjugates. Ka = [adduct]/[PBA][SHA] Stolowitz, et al, Bioconjugate Chem. 2001, 12, 229-239. Springer, et al, J. Biomol. Tech. 2003, 14(3), 183-190. Commercial PBA/SHA Conjugate Pairs • Commercially available PBA/SHA reagents: – NHS ester reacts with amines, hydrazide with aldehydes, maleimide group with thiols – Also available: pyridyl disulfide for reversible disulfide linkage to thiols, and iodoacetyl functional group to create thio ether bonds with thiols 1,2-Diol containing carbohydrates interfere with bioconjugation because the PBA-SHA interaction is reversible. Therefore, PBA/SHA conjugation is not bioorthogonal. However, PBA-SHA reactive groups are stable to hydrolysis in aqueous solution. They are useful in creating protein-protein conjugates: J. Biol. Chem. 2000, 275(12), 8952-8958. Linkages Formed by Cycloadditions A number of cycloaddition reactions are useful for bioconjugation. Normal Diels-Alder Reactions in Water The Diels-Alder reaction proceeds with high selectivity and efficiency in water: Lindstrom, U.M. Stereoselective Organic Reactions in Water. Chem. Rev. 2002,102, 2751–2771. It has been used as a bioconjugation tool for surface immobilization of oligonucleotides, the ligation of peptides, and the site-specific labeling of proteins. Waldmann: The site-specific C-terminal modification of the Rab7 protein with fluorophores by means of a normal Diels-Alder reaction in water. fluorescent probe attached at protein C- terminal thioester cysteine protecting group The C-terminal protein thioester was prepared (recombinant technology) and ligated with a short peptide containing a C-terminal hexadienyl ester to yield a Rab7 protein hexadienyl ester. A maleimide Diels Alder reaction in water provided the protein functionalized with fluorescent probes. From de Araujo, A. D.; Palomo, J. M.; Cramer, J.; Kohn, M.; Schroder, H.; Wacker, R.; Niemeyer, C.; Alexandrov, K.; Waldmann, H. Diels-Alder ligation and surface immobilization of proteins. Angew. Chem., Int. Ed. 2006, 45, 296–301. See also, Palomo, J. M. Eur. J. Org. Chem. 2010, 6303-6314. Ring Strain/Inverse Demand DA "Bioconjugation with Strained Alkenes and Alkynes ", Debets, M. F.; van Berkel, S. S.; Dommerholt, J.; Dirks, A. T. J.; Rutjes, F. P. J. T.; van Delft, F. L. Acc Chem Res 2011, 805-815. "Functionalized Cyclopropenes as Bioorthogonal Chemical Reporters", Patterson, D. M.; Nazarova, L. A.; Xie, B.; Kamber, D. N.; Prescher, J. A. J Am Chem Soc 2012, 134, 18638–18643. "Live-Cell Imaging of Cyclopropene Tags with Fluorogenic Tetrazine Cycloadditions" Yang, J.; Sečkutė, J.; Cole, C. M.; Devaraj, N. K. Angew Chem Int Ed Engl 2012, 51, 7476–7479. Abiotic strained alkenes and alkynes are relatively stable in cellular environs and can be used for bioorthogonal reactivity. trans-Cyclooctenes, norbornenes, bicyclononynes, and cyclopropenes react rapidly with electron-deficient tetrazines via inverse- electron-demand Diels−Alder reactions. Ring strain allows rapid reactions at rt. Useful for various bioorthogonal imaging applications. Avidin is a tetrameric protein found in avian egg whites. It binds to biotin (vitamin B7) with −15 a dissociation constant KD ≈ 10 M, making it one of the strongest known non-covalent bonds. via incubation Avidin-APC: stain Azide-Alkyne Cycloaddition "Click Chemistry and Bioorthogonal Reactions: Unprecedented Selectivity in the Labeling of Biological Molecules", Best, M. D. Biochemistry 2009, 48, 6571–6584. The azide-alkyne dipolar cycloaddition has revolutionized applications
Load more

Recommended publications
  • 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]
  • 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]
  • 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]
  • 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]
  • Bioorthogonal Chemistry
    Bioorthogonal Chemistry Rachel Whittaker February 13, 2013 Wednesday Literature Talk Outline What is It and Why Do We Care? Historical Background Staudinger Ligation Copper-free Click Chemistry Tetrazine Cycloadditions Other Examples Future Directions What Are We Talking About Here? “But what if the challenge [of synthesis] were inverted, wherein the target structure was relatively simple but the environment in which the necessary reactions must proceed was so chemically complex and uncontrollable that no two functional groups could combine reliably and selectively under such conditions?” – Carolyn Bertozzi, UC Berkley Acc. Chem Res., 2011, 44, 651. What Is It? Bioorthogonal chemistry- chemical reactions that neither interact with nor interfere with a biological system. Acc. Chem. Res., 2011, 44, 666. So Why Do We Care? Takes classic organic reactions and redesigns them with biological systems in mind Allows for more efficient/ non-toxic drug delivery, biological imaging, and material science Acc. Chem. Res., 2011, 44, 666. Requirements of Bioorthogonality 1. Functional groups used must be inert to biological moieties 2. FG’s must be selective for one another and nontoxic to organisms 3. Reaction must work in biological media 4. Must have very fast kinetics, particularly at low -4 -1 - concentrations and in physiological condtions (k2> 10 M s 1) 5. Helpful, but not required, if at least one FG is small Acc. Chem. Res., 2011, 44, 666. Types of Bioorthogonal Transformations* 1. Nucleophilic Additions 2. 1,3-Dipolar Cycloadditions
    [Show full text]
  • Organic Electrochemistry: Synthesis and Functionalization of Β-Lactams In
    Heterocyclic Communications 2021; 27: 32–44 Review Article Martina Bortolami, Isabella Chiarotto, Leonardo Mattiello, Rita Petrucci, Daniele Rocco, Fabrizio Vetica and Marta Feroci* Organic electrochemistry: Synthesis and functionalization of β-lactams in the twenty-first century https://doi.org/10.1515/hc-2020-0121 Keywords: cathodic reduction, anodic oxidation, azetidin- received December 01, 2020; accepted March 03, 2021 2-ones, electroorganic synthesis, electrogenerated base Abstract: Organic electrochemistry is a technique that allows for the heterogeneous redox reactions avoiding both the use of stoichiometric amounts of redox reagents and the resulting formation of stoichiometric by-pro- 1 Introduction ducts. In fact, the redox reagent in these reactions is β- ( - - ) - the electron, which is naturally eco-friendly and pro- Lactams azetidin 2 ones; Figure 1 are four membered duces no side compounds. It is therefore quite obvious heterocyclic compounds containing an amide moiety. - that electrochemistry can be classified as a “green” tech- This class of molecules is so famous in medicinal chem nology. The use of this methodology in the synthesis of istry that there is no need to describe their importance in fi - β-lactams is not a novelty, but the growing interest in this the antibiotic eld. In fact, since the discovery of peni β- class of biologically active compounds, due to the dis- cillin in 1928 by Fleming, lactam antibiotics have been covery of new fields of application (after a moment of extensively used as antibacterial agents, their use being decrease in interest due to antibiotic resistance) has less frequent in recent years due to the onset of antibiotic [ ] been a stimulus for the search for more efficient electro- resistance 1,2 .
    [Show full text]
  • Switch Peptide Via Staudinger Reaction Vol
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Infoscience - ÉcoleORGANIC polytechnique fédérale de Lausanne LETTERS 2008 Switch Peptide via Staudinger Reaction Vol. 10, No. 22 5243-5246 Natalia Nepomniaschiy,† Valerie Grimminger,‡ Aviv Cohen,† Saviana DiGiovanni,‡ Hilal A. Lashuel,*,‡ and Ashraf Brik*,† Department of Chemistry, Ben-Gurion UniVersity of the NegeV, P.O. Box 653, Beer SheVa 84105, Israel, and Brain Mind Institute, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland hilal.lashuel@epfl.ch; [email protected] Received September 29, 2008 ABSTRACT A new transformation based on the Staudinger reaction is described, and its application in the design of a novel switch element to control peptide folding is demonstrated. We found that the azide switch is activated rapidly in water to promote acyl transfer using tris(2-carboxyethyl)phosphine hydrochloride (TCEP) via the Staudinger reaction. Our findings expand the repertoire of uses of the Staudinger reaction in chemical biology and the number of available triggers for use in switch peptides. The Staudinger reaction, discovered nearly a century ago, While the aza-ylide intermediate is known to be stable in occurs between a phosphine and an azide to form an aza- organic solvents, it tends to hydrolyze rapidly in aqueous ylide.1 This transformation has been exploited in several media to furnish the primary amine and the phosphine oxide reactions of high synthetic importance wherein the aza-ylide products. In the traceless Staudinger ligation, however, the intermediate, with its highly nucleophilic nitrogen atom, reduction of the azide to amine is a competing side reaction, serves to trap various electrophiles.2 Staudinger ligation is thus reversing the capture step and leading to two peptide 4 one example of such reactions, in which an ester moiety is fragments.
    [Show full text]
  • Bioorthogonal Prodrug Activation Driven by a Strain-Promoted 1,3
    Bioorthogonal Prodrug Activation Driven by a Strain‐Promoted 1,3‐Dipolar Cycloaddition 1 Siddarth S. Matikonda, Douglas L. Orsi, Verena Staudacher, Imogen A. Jenkins, Franziska Fiedler, Jiayi Chen and Allen B. Gamble Chemical Science, 2015, 6, pp. 1212‐ 1218 (University of Otago, Dunedin, New Zealand) A. Manos‐Turvey, Wipf Group Current Literature February 28th, 2015 Alex Manos-Turvey @ Wipf Group Page 1 of 22 3/14/2015 Prodrugs for Cancer Therapies 2 Non‐selectivity in cancer treatments leads to off‐target side‐effects Prodrug activation is seen as a viable method allowing for direct drug delivery Cleavage of a deactivating linker, leading to activation Can react with off‐target sources due to hydrolysis Antibody‐Drug Conjugates (ADCs) ADCs can elicit an immune system response The linkers need to be fine tuned between stability and “cleavability” Drugs become diluted as this is dependant on cell surface receptors, leading to < potent R.V.J. Chari, M.L. Miller, W.C. Widdison, Angew. Chem., 2014, 53, 3796‐3827 Fig: http://static.cdn‐seekingalpha.com/uploads/2014/1/19447671_13889572897936_1.jpg Alex Manos-Turvey @ Wipf Group Page 2 of 22 3/14/2015 Prodrugs for Cancer Therapies 3 Antibody‐Directed Enzyme Prodrug Therapy (ADEPT) Targets an antibody‐enzyme conjugate to a cancer cell Limited to human enzymes, to avoid anti‐enzyme immune responses K.D. Bagshawe, S.K. Sharma, R.H.J. Begent, Expert Opin. Biol. Ther., 2004, 4, 1777‐1789 K.‐C. Chen, S.‐Y. Wu, Y.‐L. Leu, Z.M. Prijovich, B.‐M. Chen, H.‐E. Wang, T.‐L. Cheng, S.R. Roffler, Bioconjugate Chem., 2011, 22, 938‐948 Alex Manos-Turvey @ Wipf Group Page 3 of 22 3/14/2015 Prodrugs for Cancer Therapies 4 Bioorthogonal Chemistry Not many examples for in vitro prodrug activation Staudinger and tetrazine‐TCO (Inverse‐Electron‐Demand Diels‐Alder Cycloadditions) reactions have been used.
    [Show full text]
  • Siteselective Traceless Staudinger Ligation for Glycoprotein Synthesis Reveals Scope and Limitations
    DOI: 10.1002/cbic.201100125 Site-Selective Traceless Staudinger Ligation for Glycoprotein Synthesis Reveals Scope and Limitations GonÅalo J. L. Bernardes, Lars Linderoth, Katie J. Doores, Omar Boutureira, and Benjamin G. Davis*[a] Efficient, chemoselective reactions enable access to well-de- al stability towards hydrolases as previously demonstrated for fined post-translationally modified proteins.[1–4] One approach other natural substrates.[32,33] The construction of glycoproteins involves the positioning of a reactive moiety within a side bearing this unnatural motif may also circumvent problems en- chain that may be chemoselectively addressed (a tag-and- countered in chemoenzymatic syntheses of glycoproteins by modify approach).[5] Among functionalities, the azide group using endoglycosidases[34] and provide a linkage more resistant has received attention since it can be installed in biopolymers to hydrolysis than natural Asn-linked glycoconjugates.[35] Our (e.g., by using auxotrophic or non-natural expression as well as strategy is based on a “tag-and-modify” approach[5] and ex- metabolic and enzymatic processes[6,7]) and has been used in ploits the introduction into proteins of Aha[20] (tag) that may installation of post-translational modifications and mimics[8,9] be chemoselectively addressed (modified) using traceless Stau- and/or protein labelling[2–4, 10] in combination with Huisgen cy- dinger conditions mild enough to retain protein activity cloaddition reactions that are CuI catalysed[11,12] (CCHC) or throughout (Scheme 1). strain promoted.[13–16] The Staudinger reaction[17] is another azide-selective reaction that has been used, for example, to modify cell surface carbo- hydrates,[18,19] and to label proteins that contain azidohomoala- nine (Aha).[20] The reaction proceeds by attack of phosphine on azide to form an aza-ylid intermediate (Scheme S1A in the Supporting Information).
    [Show full text]
  • Advanced Studies on the Synthesis of Organophosphorus Compounds
    ALMA MATER STUDIORUM UNIVERSITÀ DI BOLOGNA DOTTORATO DI RICERCA IN SCIENZE CHIMICHE (XIX° ciclo) Area 03 Scienze Chimiche-CHIM/06 Chimica Organica Dipartimento di Chimica Organica “A. Mangini” Coordinatore: Chiar.mo Prof. Vincenzo Balzani Advanced Studies on the Synthesis of Organophosphorus Compounds Dissertazione Finale Presentata da: Relatore: Dott. ssa Marzia Mazzacurati Prof. Graziano Baccolini Co-relatore: Dott.ssa Carla Boga INDEX Index: Keywords…………………………………………………………….………….VII Chapter 1…………………………………………………………………………..3 GENERAL INTRODUCTION ON PHOSPHORUS CHEMISTRY 1.1 Organophosphorus Chemistry………………………………………………….4 1.1.1 Phosphines………………………………………………………………..5 1.1.2 Phosphonates……………………………………………………………..6 1.1.3 Phosphites………………………………………………………………...7 1.2 Uses of Organophosphorus Compounds………………………………………..7 1.2.1 Agricultural Application………………………………………………….8 1.2.2 Catalysis……………………………………………………………..…....9 1.2.3 Organophosphorus Conpounds in Medicine…………………………….11 1.2.4 Phosphorus in Biological Compounds…………………………………..12 1.3 References……………………………………………………………………..15 Chapter 2…………………………………………………………………………17 THE HYPERCOORDINATE STATES OF PHOSPHORUS 2.1 The 5-Coordinate State of Phosphorus……………………………………….17 2.2 Pentacoordinated structures and their non rigid character…………………….18 2.3 Permutational isomerization…………………………………………………..19 2.3.1 Berry pseudorotation……………………………………………………20 2.3.2 Turnstile rotation………………………………………………………..21 2.4 The 6-Coordinate State of Phosphorus……………………………………….22 2.5 References…………………………………………………………………......24 I Chapter
    [Show full text]
  • Chapter 5: Phosphine Reactivity Towards Azides in Water: Reduction Versus Hydrolysis
    Cover Page The handle http://hdl.handle.net/1887/67530 holds various files of this Leiden University dissertation. Author: Gential, G.P.P. Title: Self adjuvanting immunopeptides : design and synthesis Issue Date: 2018-12-17 Chapter 5: Phosphine reactivity towards azides in water: Reduction versus hydrolysis Published partially: Pawlak J.B., Gential, G. P. P. et al. Bioorthogonal Deprotection on the Dendritic Cell Surface for Chemical Control of Antigen Cross-Presentation Angew.Chem.Int. Ed. 2015, 54,5628 –5631 Introduction In the field of bioorganic synthesis, azides are commonly used as masked functionalities to protect amines. Azides are easily introduced by substitution reactions or can be obtained from amines by diazo transfer. Azides can withstand a variety of reaction conditions and are easily converted into amines by several types of reduction, including the Staudinger reaction1,2. Reaction of an azide with a trialkyl- or triarylphosphine proceeds via an iminophosphorane that upon hydrolysis leads to the corresponding amine (Figure 1). The combination of azide and Staudinger reaction was given a reappraisal by the emergence of bioorthogonal chemistry3. This field of research aims to the selective detection of a specific biomolecule in living or biological systems4. To attain this goal the biomolecule of interest should be provided with a reactive group that is inert in biological systems but selectively reacts with a reporter group under physiological conditions5,6. The azide function is small, relatively stable, abiotic and essentially non-cytotoxic while incorporation of an azide into the biomolecule of interest allows a number of selective reactions with probes such as reporter molecules.
    [Show full text]