In situ click chemistry
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In situ Click chemistry. Mgr. Juraj Dobia š KOCH, PRIF UK . What is Click Chemistry ?. joining molecules by an „ ideal chemical reaction “ fast, irreversible reaction, simple conditions starting materials are readily available, stable (biocompatible )

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In situ click chemistry

In situ Click chemistry

Mgr. JurajDobiaš


In situ click chemistry

What is Click Chemistry ?

joining molecules by an „ideal chemical reaction“

  • fast, irreversible reaction, simple conditions

  • starting materials are readily available, stable (biocompatible)

  • high yielding, high atom economy, wide application

  • large thermodynamic driving force to give predictable outcome

  • easy work-up and product isolation

  • preferably proceeding in water, insensitive to oxygen

  • thebest by somefusionreaction:

Synthesis of 1 2 3 triazoles
Synthesis of 1,2,3-triazoles

  • ThermalHuisgen [3+2] cycloaddition

    • 80-120°C, 12-24h, both regioisomers ca 1/1 E#A= 24-26 kcal/mol

  • Cu(I) catalyzed(CuSO4 / sodium L-ascorbate)

    • only 1,4-regioisomer, high yield, rt, t-BuOH / water environment E#A= 15 kcal/mol(106 times faster than Huisgen r.)

  • Ru catalyzed (Cp*RuCl(PPh3)2)

    • mainly 1,5-regioisomer

1950-70 Huisgen

2002, Fokin, SharplessMelda

2005, FokinShrapless

Click chemistry exploitation
Click Chemistry Exploitation

  • Material sciences(copolymers, functionalized surfaces, adhesives, dendrimers, large macrocycles, ....)

  • Bioorganic chemistry (biosensors, bioconjugates: tagging of proteins, nucleotides or in situ whole organisms, SPAAC – no metal)

  • Drug development – Medicinal Chemistry

In situ click chemistry

MMps inhibitors




MMP7 selective, low mcM inhibitors

Org. Lett. 8 2006 3821-24.

In situ click chemistry tds target driven synthesis
In Situ Click Chemistry (TDS) target driven synthesis

TDS reduces the number of inactive compounds

Compensate the lack of precision in the predictive ability of in Silico chemistry

In situ AA Click chemistry is completely biocompatible, uses irreversible reaction to unite reagents inside the protein´s binding pocket

Target will pick best fitting ligandsfrom diverse sets of chemical building blocks

Significant portion of the activation barrier is entropic(pieces have to approach each other in precisely the right orientation), pre-assembly of building blocks on the target active site can accelerate cycloaddition.

DDT 9 2004 348.

In situ click chemistry
Observation of the controlled assembly of preclickcomponents in the in situ click chemistrygeneration of a chitinase inhibitor

  • chitinaseinhibitorsfight against infectious and inflammatorydiseases – onchocerciasis.

  • screeningofover 10,000 extracts from soil microorganisms

2013 PNAS 110 15892-97

In situ click
In situ click

Triazole komplex
Triazole komplex


Captured transition state
Capturedtransition state

  • Alkene doesn’tcocrystalyze without azide even at high concentration – induced fit.

  • Different pose of azide with and without alkene – double induced fit.




  • Identified triazole inhibitor of chinase B by in situ click chemistry approach.

  • Solved crystal structure of transition state with alkene analog.

  • Performed DFT calculations, but did not observe any enthaplic barrier decrease.

  • Confirmed in situ click chemistry principle that increase in reaction rate is caused by entropic factors and greater effective concentration.

  • Solved crystal structures that demonstrate protein flexibility and lack of in silico methods accuracy.