YACHAY TECH

ORGANIC CHEMISTRY II

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

IN SITU CLICK CHEMISTRY

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 Figure 1. Schematic illustration of in situ click chemistry
synthesis approach [3]. used to develop enzyme or protein inhibitors

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, step 2.

Example

Discovery of bioactive molecules,

termed in situ click chemistry, for
the elucidation of novel HIV-1-Pr
inhibitors. The goal of in situ click
chemistry is to accelerate the
identification of novel
pharmaceutical candidates through
involvement of a biological target in
the selection and covalent
assembly of its own inhibitors. Figure 4. Principal mechanism of the reaction.

Although the concept has been previously demonstrated by several researchers, the in situ click
chemistry approach is unique in that it relies on the completely bio-orthogonal 1, 3-dipolar
cycloaddition of organic azides and alkynes. The majority of this reactions are characterized by a
simple mechanism in this case the bond between the molecules occurs between the N3 of the second
molecule and the triple bond of the first molecule. This reaction follow the scheme of formation of
tryzol (aromatic molecule characterized by the presence of 3 nitrogens). [6]

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
[6] Whiting, M., Muldoon, J., Lin, Y., Silverman, S., Lindstrom, W., Olson, A., Kolb, H., Finn, M.,
Sharpless, K., Elder, J. and Fokin, V. (2006). Inhibitors of HIV-1 Protease by Using In Situ Click
Chemistry. Angewandte Chemie, 118(9), pp.1463-1467