YACHAY TECH

ORGANIC CHEMISTRY II

Names: Clara Carrera, Cynthia Soto, Antoni Paez, Dolores Parra & David Moreno
Professor: Kamil Makowsky

IN SITU CLICK CHEMISTRY

Definition

Click chemistry was developed by the Nobel Barry Sharpless and his team in 2001. In his own
words, the click chemistry is “the use of chemical building blocks with built-in high-energy
content to drive a spontaneous and irreversible linkage reaction with appropriate
complementary sites in other blocks" [1]. He expanded the idea of click chemistry to a more
developed strategy: In situ click chemistry, which is the use of chemical and biological receptor
structures as templates to guide the formation of click chemistry products [2].That is, protein
binding sites, supramolecular complexes, or functionalized surfaces are used as reaction
vessels to direct the in situ formation of potentially functional click chemistry products. The
products might be biological inhibitors, molecular-electronics components, sensor probes,
nonlinear optical materials, light-harvesting compounds, or compounds with any number of
other useful properties [2].

The reaction that occur in an in situ click chemistry is a 1,3-dipolar cycloaddition of organic
azides and alkynes in a kinetically-controlled target guided synthesis approach [3].

Figure 1. Schematic illustration of in situ click chemistry used to develop enzyme or protein inhibitors.

Importance of the application

The importance of in situ click chemistry lies in the fact that this chemistry has an efficient
approach in the discovery of new candidates to drugs. Since it is possible to identify high
affinity inhibitor related conformations which are not detected by traditional methods.
These findings have interesting implications for drug discovery, as it is possible to trap a
flexible enzyme in a minor abundance conformation by an inhibitor, which is formed inside its
binding pockets through the irreversible reaction of complementary building blocks. [5].
Process of the in situ click chemistry
Step 1. Synthesis of building blocks bearing reactive groups X and Y

Figure 2. Building blocks, step 1.

Step 2. Incubation of building blocks with the target protein. The protein binds initially the
building blocks with the highest affinity. The enforced propinquity of the groups X (N3) and Y
(CΞC-H) accelerates the irreversible reaction with each other resulting in the formation of a
covalent bond (triazole) between the two building blocks.
The newly generated biligand molecule shows higher affinity compared with corresponding
monovalent building blocks [5]

Figure 3. Incubation of building blocks with the target protein.

Examples

References

[1] Kolb, H., Finn, M. and Sharpless, K. (2001). Click Chemistry: Diverse Chemical Function
from a Few Good Reactions. Angewandte Chemie International Edition, 40(11), pp.2004-
2021.

[2] Pubs.acs.org. (2018). C&EN: COVER STORY - IN SITU CLICK CHEMISTRY. [online]
Available at: http://pubs.acs.org/cen/coverstory/8006/8006clickchemistry.html [Accessed 21
Apr. 2018].

[3] Mamidyala, S. and Finn, M. (2010). In situ click chemistry: probing the binding landscapes
of biological molecules. Chemical Society Reviews, 39(4), p.1252.

[4] Manetsch et al. (2004). In Situ Click Chemistry: Enzyme Inhibitors Made to Their
Own Specifications. JACS articles, 126 (40), 12809–12818. doi 10.1021/ja046382g
[5] Sharples, K., Manetsch, R. (2006). In situ click chemistry: a powerful means for leads
discovery. Expert Opinion on Drug Discovery, 1, 525-538. doi 10.1517/17460441.1.6.525