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Recent Advances in Copper Catalyzed Azide/Alkyne Cycloadditions: Prototypical “Click” Reactions Shane Mangold Kiessling Group February 14th 2008.

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Presentation on theme: "Recent Advances in Copper Catalyzed Azide/Alkyne Cycloadditions: Prototypical “Click” Reactions Shane Mangold Kiessling Group February 14th 2008."— Presentation transcript:

1 Recent Advances in Copper Catalyzed Azide/Alkyne Cycloadditions: Prototypical “Click” Reactions Shane Mangold Kiessling Group February 14th 2008

2 2 Historical Perspective of Azide/Alkyne Cycloadditions L. Pauling. Proc. Natl. Acad. Sci. USA 1933, 19, ; Huisgen, R. Angew. Chem. Int. Ed. 1963, 2, Sharpless, K.B. et al. Angew. Chem. Int. Ed 2002, 41, ; Meldal,M.J. et al. J. Org. Chem. 2002, 67, Dipolar nature of azide first recognized by Linus Pauling Mechanism of 1,3-dipolar cycloaddition of azides and alkynes pioneered by Rolf Huisgen Copper catalyzed 1,3-Dipolar cycloaddition by Sharpless/Meldal

3 3 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,

4 4 Reactions that meet the “Click” Criteria Kolb, H.C.; Finn, M.G.; Sharpless, B.K. Angew. Chem. Int. Ed. 2001, 40,

5 5 Copper Catalyzed Azide/Alkyne Cycloaddition (CuAAC) Thermodynamic and kinetically favorable (50 and 26 kcal/mol, respectively) Regiospecific Chemoselective 10 7 rate enhancement over non- catalyzed reaction Triazole stable to oxidation and acid hydrolysis Rostovtsev et al. Angew. Chem. Int Ed. 2002, 41,

6 6 CuAAC Catalytic Cycle Himo, F. et al. J. Am. Chem. Soc, 2005, 127, Ahlquist, M., Fokin, V.V. Organometallics 2007, 26, kcal/mol 18 kcal/mol

7 7 CuAAC Chemistry Applications Peptide/Protein Modification Therapeutics Combinatorial Synthesis Polymer Functionalization Materials/Surface Chemistry

8 8 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. Tetrahedron 1988, 44,

9 9 Synthesis of Tetrapeptide Analogue cyclo- [Pro-Val-  (triazole)-Pro-Tyr] Cyclo-[ L Pro- L Val- L Pro- L Tyr] 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,

10 10 1,2,3-Triazoles as Peptide Bond Isosteres 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 Kolb, H.C., Sharpless, B.K. Drug. Disc. Today. 2003, 8, Å 5.1 Å

11 11 Bock, V.D., et al. Org. Lett. 2006, 8, Retrosynthesis

12 12 Bock, et al. Org. Lett. 2006, 8, Synthesis of Cyclic Tetrapeptide Analogue

13 13 Bock, V.D. et al. Org. Biomol. Chem., 2007, 5, Tyrosinase Inhibition Compound Tyrosinase Activity IC 50 / mM Cyclo-[Pro-Tyr-Pro-Val]1.5 Triazole analogue 20.6 Triazole analogue 30.5 Triazole analogue 41.6

14 14 Outline Peptide/Protein Modification – Peptide Macrocyclization Therapeutics –Multivalent carbohydrate vaccines Inhibitors Chemoenzymatic Functionalization Materials Science/Polymers

15 15 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,

16 16 Wan, Q., Chen, J., Chen, G., Danishefsky, S.J. J. Org. Chem. 2006, 71, CuAAC of Multivalent Carbohydrate Peptide Conjugate

17 17 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,

18 18 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,

19 19 Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, Synthesis of Man4

20 20 Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, Template Synthesis of Man-4 Cluster

21 21 Wang, J., Li, H., Zou, G., Wang, L-X. Org. Biomol. Chem., 2007, 5, Synthetic Vaccine Conjugate

22 22 Outline Protein Molecular Architecture – Peptide Macrocyclization Multivalent Architecture –Vaccine Conjugates Inhibitors –Combinatorial Chemistry Chemoenzymatic Functionalization Materials Science/Polymers

23 23 Inhibitors of HIV-Protease by CuAAC HIV-Protease cleaves proteins to yield active HIV virus Amprenavir is HIV-protease inhibitor used clinically since Develop Amprenavir analogue using CuAAC for combinatorial screening Folkin, V, V. et al. J. Med. Chem. 2006, 49,

24 24 Folkin, V.V. et al. J. Med. Chem. 2006, 49, Synthesis of HIV Protease Inhibitor

25 25 Synthesis of HIV Protease Inhibitor Folkin, V.V. et al. J. Med. Chem. 2006, 49,

26 26 Inhibitor Optimization Folkin, V.V. et al. J. Med. Chem. 2006, 49,

27 27 Outline Protein Molecular Architecture – Peptide Macrocyclization Multivalent Architecture –Vaccine Conjugates Inhibitors –Combinatorial Chemoenzymatic Functionalization –Metabolic Engineering –Antibiotic Derivatization Polymers/Materials Science

28 28 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,

29 29 Metabolic Oligosaccharide Engineering Wong, C-H., et al. Proc. Natl. Acad. Sci. 2006, 103,

30 30 Intracellular Fucosylation Fluorescent probe WGA-Dye (Golgi Marker) Overlay Wong, C-H., et al. Proc. Natl. Acad. Sci. 2006, 103,

31 31 Chemoselective Functionalization of Antibiotics by Glycorandomization Glycorandomization: Chemoenzymatic glycodiversity of natural product based scaffolds Thorson, J.S. et al. Org. Lett. 2005, 7,

32 32 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,

33 33 Glycorandomization of Vancomycin Thorson, J.S. et al. Org. Lett. 2005, 7,

34 34 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

35 35 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,

36 36 Transfer Printing of DNA Using Dendritic Architectures Reinhoudt, D.A. et al. ChemBioChem, 2007, 8,

37 37 Synthesis of Alkyne Modified DNA Monomer Reinhoudt, D.A. et al. ChemBioChem, 2007, 8,

38 38 Reinhoudt, D.A. et al. J. Am. Chem. Soc. 2007, 129, Surface Patterning of ssDNA Oxime Functionalized TemplateCuAAC Functionalized Template

39 39 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 K i determination Krasinski, A. et al. J. Am. Chem. Soc. 2005, 127,

40 40 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, Whiting, M. et al. Angew. Chem. Int. Ed. 2006, 45, Mocharla, V.P. et al. Angew. Chem. Int. Ed. 2005, 44,

41 41 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

42 42 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


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