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Recent Advances in Copper Catalyzed Azide/Alkyne Cycloadditions: Prototypical “Click” Reactions. Shane Mangold Kiessling Group February 14th 2008. Historical Perspective of Azide/Alkyne Cycloadditions. 1933- Dipolar nature of azide first recognized by Linus Pauling.

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recent advances in copper catalyzed azide alkyne cycloadditions prototypical click reactions

Recent Advances in Copper Catalyzed Azide/Alkyne Cycloadditions: Prototypical “Click” Reactions

Shane Mangold

Kiessling Group

February 14th 2008

historical perspective of azide alkyne cycloadditions
Historical Perspective of Azide/Alkyne Cycloadditions

1933- Dipolar nature of azide first recognized by Linus Pauling

1960- Mechanism of 1,3-dipolar cycloaddition of azides

and alkynes pioneered by Rolf Huisgen

2001- Copper catalyzed 1,3-Dipolar cycloaddition by Sharpless/Meldal

L. Pauling. Proc. Natl. Acad. Sci. USA 1933, 19, 860-867; Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, 633-696

Sharpless, K.B. et al. Angew. Chem. Int. Ed 2002, 41, 2596-2599; Meldal,M.J. et al. J. Org. Chem. 2002, 67, 3057-3064

defining a click chemistry reaction
Defining a “Click” Chemistry Reaction

“ A click reaction must be modular, wide in scope, high yielding, create only inoffensive by-products (that can be removed without chromatography), are stereospecific, simple to perform and that require benign or easily removed solvent. ”

- Barry Sharpless

Kolb, H.C.; Finn, M.G.; Sharpless, B.K. Angew. Chem. Int. Ed. 2001, 40, 2004-2021.

reactions that meet the click criteria
Reactions that meet the “Click” Criteria

Kolb, H.C.; Finn, M.G.; Sharpless, B.K. Angew. Chem. Int. Ed. 2001, 40, 2004-2021.

copper catalyzed azide alkyne cycloaddition cuaac
Copper Catalyzed Azide/Alkyne Cycloaddition (CuAAC)
  • Thermodynamic and kinetically favorable (50 and 26 kcal/mol, respectively)
  • Regiospecific
  • Chemoselective
  • 107 rate enhancement over non-catalyzed reaction
  • Triazole stable to oxidation and acid hydrolysis

Rostovtsev et al. Angew. Chem. Int Ed. 2002, 41, 2596-2599

cuaac catalytic cycle
CuAAC Catalytic Cycle

23 kcal/mol

18 kcal/mol

Himo, F. et al. J. Am. Chem. Soc, 2005, 127, 210-216.

Ahlquist, M., Fokin, V.V. Organometallics2007, 26, 4389-4391.

cuaac chemistry applications
CuAAC Chemistry Applications
  • Peptide/Protein Modification
  • Therapeutics
  • Combinatorial Synthesis
  • Polymer Functionalization
  • Materials/Surface Chemistry
cuaac as a route to cyclic tetrapeptide analogues
CuAAC as a Route to Cyclic Tetrapeptide Analogues
  • Cyclic peptides important antimicrobial agents
  • More stable to enzymatic degradation and better cellular uptake than linear chain form
  • Conformational restriction allows better understanding of receptor-ligand interactions
  • Difficult to synthesize due to strain energy of cyclization in transition state

Rich, D.H. et al. Tetrahedron1988, 44, 685-695

synthesis of tetrapeptide analogue cyclo pro val triazole pro tyr
Synthesis of Tetrapeptide Analogue cyclo-[Pro-Val-(triazole)-Pro-Tyr]
  • Cyclo-[LPro-LVal-LPro-LTyr] is a tyrosinase inhibitor isolated from L. helveticus
  • Previous attempts at synthesis had failed due to epimerization upon cyclization
  • Hypothesize ring contraction mechanism of CuAAC may help promote cyclization

Van Maarseveen, J.H. et al. Org. Lett. 2006, 8, 919-922

1 2 3 triazoles as peptide bond isosteres
1,2,3-Triazoles as Peptide Bond Isosteres

3.9 Å

  • Triazole and peptide bond both possess large dipole (5D, 3.7D, respectively)
  • N2 and N3 lone pairs serve as hydrogen bond acceptors
  • C distance comparable
  • Triazole mimics planarity of amide bond

5.1 Å

Kolb, H.C., Sharpless, B.K. Drug. Disc. Today. 2003, 8, 1128-1136.

retrosynthesis
Retrosynthesis

Bock, V.D., et al. Org. Lett. 2006, 8, 919-922

synthesis of cyclic tetrapeptide analogue
Synthesis of Cyclic Tetrapeptide Analogue

Bock, et al. Org. Lett. 2006, 8, 919-922

tyrosinase inhibition
Tyrosinase Inhibition

Bock, V.D. et al. Org. Biomol. Chem., 2007, 5, 971-975

outline
Outline
  • Peptide/Protein Modification
    • Peptide Macrocyclization
  • Therapeutics
    • Multivalent carbohydrate vaccines
  • Inhibitors
  • Chemoenzymatic Functionalization
  • Materials Science/Polymers
anticancer vaccines through extended cycloaddition chemistry
Anticancer Vaccines Through Extended Cycloaddition Chemistry
  • To exploit antitumor immune response, induce antibodies against carbohydrate antigens
  • Protein Scaffold upon which carbohydrates are attached is important for eliciting antibody production
  • Drawback is that monovalent carbohydrate/antibody interactions are weak

Wan, Q., Chen, J., Chen, G., Danishefsky, S.J. J. Org. Chem. 2006, 71, 8244-8249

cuaac of multivalent carbohydrate peptide conjugate
CuAAC of Multivalent Carbohydrate Peptide Conjugate

Wan, Q., Chen, J., Chen, G., Danishefsky, S.J. J. Org. Chem. 2006, 71, 8244-8249.

template assembled oligosaccharide epitope mimics
Template-Assembled Oligosaccharide Epitope Mimics
  • 2G12 antibody targets oligomannose cluster (Man-9) present on HIV-1 gp120
  • Recognizes terminal Man1-2Man residues
  • Man-4 had comparable affinity to the antibody as that of Man-9 moeity

Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, 1529-1540.

template assembled oligosaccharide epitope mimics18
Template-Assembled Oligosaccharide Epitope Mimics
  • Cyclic decapeptide shown to be better immunogen than linear form
  • T-helper peptide previously shown to increase immunogenicity of conjugate
  • Synthesize template consisting of decapeptide conjugated with T-helper peptide epitopes for IgG antibody production.

Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, 1529-1540.

synthesis of man4
Synthesis of Man4

Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, 1529-1540.

template synthesis of man 4 cluster
Template Synthesis of Man-4 Cluster

Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, 1529-1540.

synthetic vaccine conjugate
Synthetic Vaccine Conjugate

Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, 1529-1540

outline22
Outline
  • Protein Molecular Architecture
    • Peptide Macrocyclization
  • Multivalent Architecture
    • Vaccine Conjugates
  • Inhibitors
    • Combinatorial Chemistry
  • Chemoenzymatic Functionalization
  • Materials Science/Polymers
inhibitors of hiv protease by cuaac
Inhibitors of HIV-Protease by CuAAC
  • HIV-Protease cleaves proteins to yield active HIV virus
  • Amprenavir is HIV-protease inhibitor used clinically since 1997.
  • Develop Amprenavir analogue using CuAAC for combinatorial screening

Folkin, V, V. et al. J. Med. Chem. 2006, 49, 7697-7710

synthesis of hiv protease inhibitor
Synthesis of HIV Protease Inhibitor

Folkin, V.V. et al. J. Med. Chem. 2006, 49, 7697-7710

synthesis of hiv protease inhibitor25
Synthesis of HIV Protease Inhibitor

Folkin, V.V. et al. J. Med. Chem. 2006, 49, 7697-7710

inhibitor optimization
Inhibitor Optimization

Folkin, V.V. et al. J. Med. Chem. 2006, 49, 7697-7710

outline27
Outline
  • Protein Molecular Architecture
    • Peptide Macrocyclization
  • Multivalent Architecture
    • Vaccine Conjugates
  • Inhibitors
    • Combinatorial
  • Chemoenzymatic Functionalization
    • Metabolic Engineering
    • Antibiotic Derivatization
  • Polymers/Materials Science
glycoproteomic probes for imaging of fucosylated glycans in vivo
Glycoproteomic Probes for Imaging of Fucosylated Glycans in vivo
  • Develop probe that is fluorescently active when undergoing reaction, whereas unreacted reagent remains traceless
  • Fluorescent signal of naphthalimides modulated by electron donating properties of triazole
  • Incorporate azidofucose analog into glycoproteins using biosynthetic pathway

Wong, C.H. et al. Proc. Natl. Acad. Sci.2006, 103, 12371-12376

metabolic oligosaccharide engineering
Metabolic Oligosaccharide Engineering

Wong, C-H., et al. Proc. Natl. Acad. Sci.2006, 103, 12371-12376.

intracellular fucosylation
Intracellular Fucosylation

Fluorescent

probe

WGA-Dye

(Golgi Marker)

Overlay

Wong, C-H., et al. Proc. Natl. Acad. Sci.2006, 103, 12371-12376

chemoselective functionalization of antibiotics by glycorandomization
Chemoselective Functionalization of Antibiotics by Glycorandomization
  • Glycorandomization: Chemoenzymatic glycodiversity of natural product based scaffolds

Thorson, J.S. et al. Org. Lett. 2005, 7, 1513-1515

glycorandomization of vancomycin
Glycorandomization of Vancomycin
  • Vancomycin: glycosylated natural product isolated from the bacteria Amycolatopsis orientalis
  • Last defense against infections caused by methicillin-resistant Gram-positive bacteria such as Stapholococcus aureas
  • Chemical and chemoenzymatic alterations to vancomycin impact both molecular target and organism specificity

vancomycin

Hubbard, B.K., Walsh, C.T. Angew. Chem. Int. Ed. 2003, 42, 730-765

glycorandomization of vancomycin33
Glycorandomization of Vancomycin

Thorson, J.S. et al. Org. Lett. 2005, 7, 1513-1515

outline34
Outline
  • Protein Molecular Architecture
    • Peptide Macrocyclization
  • Multivalent Architecture
    • Vaccine Conjugates
  • Inhibitors
    • Combinatorial
  • Chemoenzymatic Functionalization
    • Metabolic Engineering
    • Antibiotic Derivatization
  • Polymers/Materials Science
    • Surface Patterning with Dendritic Scaffolds
dna microarrays using cuaac
DNA Microarrays Using CuAAC
  • DNA microarrays (DNA chips) useful for large scale parallel analysis of gene expression
  • Chemistry used for immobilization is limited by cross-reactivity on surface
  • Efficiency and Bioorthogonality of CuAAC could overcome existing limitations of immobilization

Reinhoudt, D.A. et al. ChemBioChem, 2007, 8, 1997-2002

transfer printing of dna using dendritic architectures
Transfer Printing of DNA Using Dendritic Architectures

Reinhoudt, D.A. et al. ChemBioChem, 2007, 8, 1997-2002

synthesis of alkyne modified dna monomer
Synthesis of Alkyne Modified DNA Monomer

Reinhoudt, D.A. et al. ChemBioChem, 2007, 8, 1997-2002

surface patterning of ssdna
Surface Patterning of ssDNA

Oxime Functionalized Template

CuAAC Functionalized Template

Reinhoudt, D.A. et al. J. Am. Chem. Soc.2007, 129, 11593-11599

future directions target guided synthesis tgs
Future Directions: Target Guided Synthesis (TGS)
  • Target Guided synthesis uses enzyme for assembling its own inhibitors in situ
  • Kinetically controlled approach by irreversible formation of product
  • Chemoselectivity of azide/alkyne reaction eliminates byproducts that may alter enzyme
  • In situ generated inhibitors separated by LCMS and re-synthesized for Ki determination

Krasinski, A. et al. J. Am. Chem. Soc. 2005, 127, 6686-6692

future directions
Future Directions
  • Target Guided Synthesis has created the most potent inhibitors of HIV Protease, Acetylcholine esterase, and Carbonic Anhydrase known.
  • May lead to a revolution in drug discovery

Manetsch, R. et al. J. Am. Chem. Soc. 2004, 126, 12809-12818

Mocharla, V.P. et al. Angew. Chem. Int. Ed. 2005, 44, 116-120

Whiting, M. et al. Angew. Chem. Int. Ed. 2006, 45, 1435-1439

conclusions
Conclusions
  • Stepwise, non-concerted mechanism accounts for 1,4 regiospecificity
  • Chemoselectivity of azide/alkyne cycloaddition allows for bioorthogonal conjugation and combinatorial screening
  • Electronic properties of triazole serve as peptide bond mimics and modulate fluorescence of dyes
  • High thermodynamic stability of triazole offers superior control for surface functionalization
acknowledgements
Laura Kiessling

Hans Reich

Kathleen Myhre

Kiessling Lab Members

Practice Talk Attendees

Chris Shaffer

Christie McGinnis

Emily Dykhuizen

Raja Annamalai

Chris Brown

Katie Garber

Margaret Wong

Aim Tongpenyai

Becca Splain

Acknowledgements