PYRROC an alternative to Copper catalysts in strain promoted - - PowerPoint PPT Presentation

▶
pyrroc
SMART_READER_LITE
LIVE PREVIEW

PYRROC an alternative to Copper catalysts in strain promoted - - PowerPoint PPT Presentation

Aug 18, 2022 252 likes •478 views

PYRROC an alternative to Copper catalysts in strain promoted azide-alkyne cycloaddition reactions 01.06.2016 Dr. Corinna Grst OSC OrganoSpezialChemie GmbH Azide Alkyne Cycloaddition Huisgen (1960er): 1,3-dipolar cycloaddition

slide-1
SLIDE 1

PYRROC

an alternative to Copper catalysts in strain promoted azide-alkyne cycloaddition reactions

01.06.2016

  • Dr. Corinna Gröst

OSC OrganoSpezialChemie GmbH

slide-2
SLIDE 2
  • Huisgen (1960er): 1,3-dipolar cycloaddition
  • Sharpless and Meldal (2002):
  • Insensitivity against water or oxygen
  • Broad applicability
  • High yield
  • No or easily separable side-products

2

Click Chemistry:

  • Angew. Chem., Int. Ed., 1963, 2, 565. Angew. Chem., Int. Ed., 2002, 41, 2596. J. Org. Chem., 2002, 67, 3057. Angew. Chem., Int. Ed., 2001, 40, 2004.

Azide Alkyne Cycloaddition

Cu(I) catalysis

slide-3
SLIDE 3

3

  • Chem. Ber., 1961, 94, 3260. J. Am. Chem. Soc., 2004, 126, 15046.
  • Cu(I) cytotoxic
  • click reaction through ring strain

Wittig, Krebs (1961): Bertozzi (2004):

SPAAC

strain-promoted azide-alkyne cycloaddition

slide-4
SLIDE 4

4

  • J. Am. Chem. Soc., 2008, 130, 11486. J. Am. Chem. Soc., 2009, 131, 8121. ChemBioChem, 2011, 12, 1912. Chem. - A Europ. J., 2012, 18, 822.
  • Angew. Chem., Int. Ed., 2010, 49, 9422. Org. Lett., 2014, 16, 1634. J. Org. Chem., 2012, 77, 2093.

k (in M-1s-1) determined through 1H-NMR measurement in the reaction with benzyl azide. * calc. for the reaction with MeN3.

reactivity

Cyclooctynes

calc.:

slide-5
SLIDE 5

5

Cyclooctynes

OCT BCN PYRROC

  • Org. Biomol. Chem., 2015, 13, 3866.
slide-6
SLIDE 6

6

PYRROC

  • Org. Biomol. Chem., 2015, 13, 3866.
slide-7
SLIDE 7

7

PYRROC

  • Org. Biomol. Chem., 2015, 13, 3866.
slide-8
SLIDE 8

8

PYRROC

PYRROC 12

alkyne

  • Org. Biomol. Chem., 2015, 13, 3866.
slide-9
SLIDE 9

9

Zeit / s 500 1000 1500 2000 60 80 100 120 140 160 180 200 220 15 mM y = 0.058 x + 72.84 R2 = 0.993 1/[44] / M-1

k = 0.058 ± 0.004 M-1 s-1

PYRROC

Time / sec 1/[PYRROC] / M-1

  • Org. Biomol. Chem., 2015, 13, 3866.

PYRROC 12

slide-10
SLIDE 10

10

FRET

FRET

Förster resonance energy transfer

exitation emission emission fluorophore 1 fluorophore 1 fluorophore 2 Fluorophore 1 Fluorophore 2

slide-11
SLIDE 11

11

  • Org. Biomol. Chem., 2015, 13, 3866.
slide-12
SLIDE 12

12

PYRROC

Wellenlänge / nm 500 520 540 560 580 600 620 640 Intensität / a.u. 100 200 300 400 Alkin 50 BODIPY(TMR)-Azid Triazol 51 Zeit / min 20 40 60 80 100 120 0,0 0,5 1,0 1,5 2,0 2,5 3,0 PBS, 3 µM y = 1.40 *104 x + 3.74 * 105 x = Zeit/ min R2 = 0.99 1/[52] / 106 * M-1

k = 234 ± 2 M-1 s-1

BODIPY(FL)-PYRROC BODIPY(TMR)-azide Triazole Alkyne Time / min 1/[BODIPY(FL)-PYRROC]/ 106 M-1

Intensity / a.u. Intensity / a.u. Wave length / nm Wave length / nm

  • Org. Biomol. Chem., 2015, 13, 3866.
slide-13
SLIDE 13

13

  • Org. Biomol. Chem., 2015, 13, 3866.

PYRROC

k = 13.9 ± 0.3 M-1 s-1 k = 930 ± 26 M-1 s-1 k = 492 ± 43 M-1 s-1

measured in PBS (phosphate buffered saline)

slide-14
SLIDE 14

14

Potential applications

Biochemistry Fluorescence-labelling of biomolecules in cells in Organisms Bioorthogonal reactions with ≥ 2 functionalities in cells Material Science Synthesis of macromolecules and polymers Drug discovery Synthesis of compound libraries Lead structure optimization Target Guided Synthesis (TGS)

slide-15
SLIDE 15

Labelling of glycanes, proteins, enzymes e.g. live cell imaging of cell membrane

15

  • J. Am. Chem. Soc., 2008, 130, 11486. Chem. Rev., 2013, 113, 4905. ChemBioChem, 2015, 16, 1314. J. Am. Chem. Soc., 2003, 125, 4686.

Fluorescence-labelling of biomolecules

fluorescent cell membrane

+ highly reactive PYRROC in aq. media + functunalization to fit special needs (in solubility, size, reaction rate)

with Pyrroc:

slide-16
SLIDE 16

16

  • Angew. Chem., Int. Ed., 2012, 51, 6320. Chem. Soc. Rev., 2007, 36, 1249-62. Org. Biomol. Chem., 2012, 10, 548.

Bioorthogonal reactions

  • rthogonal synthetic handles

sequential biomolecule conjugations e.g. development of biotherapeutics, antibody–drug conjugates, synthetic vaccines Functionalization via SPAAC Functionalization via CuAAC Reaction site for albumine Additional Functionalization possible

c

slide-17
SLIDE 17

17

  • Angew. Chem., Int. Ed., 2008, 46, 1018. Nat. Chem., 2011, 3, 925. Chem. Soc. Rev., 2007, 36, 1249-62. Pharm. Res. 2012, 29, 902.

Synthesis of macromolecules

+ more functionalization and branching possible + interesting new properties + no side products (Cu,…) Polymers Hydrogels

slide-18
SLIDE 18

18

Compound libraries

Synthesis of compound libraries and lead structure optimization through high-throughput screening

Compound library

+ fast reaction + no side products (Cu,…) + new scaffold

slide-19
SLIDE 19

19

Target Guided Synthesis

  • Angew. Chem., Int. Ed., 2002, 41, 1053. Angew. Chem., Int. Ed., 2010, 49, 6817. Angew. Chem., Int. Ed., 2006, 45, 1435.

Reaction at the active side of the enzyme e.g. screening for inhibitors of Histonedeacetylase, HIV-1 Protease or Acetylcholinesterase

slide-20
SLIDE 20

Reaction on protein surfaces inhibition of protein-protein interactions + large molecules synthesized inside the cell + fast reaction + selective + Isomer-free preparation of inhibitors favorable

20

Target Guided Synthesis

PYRROC

slide-21
SLIDE 21

21

Fluorescence-labelling of biomolecules Bioorthogonal reactions

Functionalization via SPAAC Functionalization via CuAAC Reaction site for albumine

Synthesis of macromolecules

Drug discovery

Compound library

Summary

Additional Functionalization possible

k up to 930 M-1 s-1