In situ “click” chemistry

Lewis, W. G. Green, L. G. Grynszpan, F. Radic, Z. Carlier, P. R. Taylor, R Finn, M. G. Sharpless, K. B. Click chemistry in situ Acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew. Chem. Int. Ed. 2002,41,1053-1057. 

Click chemistry in situ acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew Chem Int Ed 41 1053-1057... 

Using SPR screening, crystallography, click-chemistry in situ and rational design, we have identified EthR drug-like inhibitors that increase the efficacy of ethionamide by at least 25-fold in vitro and 3-fold... 

Table 7.1 Published examples of] n situ medicinal chemistry in situ DCC (2006-mid-2007) and in situ Click chemistry (since its inception in 2002-mid-2007).

Figure 14.8 Use of the copper(l)-mediated alkene-azide 1,3-cycloaddition ("click" chemistry) in both organic solvent and aqueous solvent systems. The aqueous system, with in situ generation of copper(l) from copper(II), is less sensitive to oxygen.

Figure 2.4 Application of in situ click chemistry in the discovery of new ligands.

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

For certain substrates, Fokin, Van der Eycken, and coworkers subsequently discovered that the azidation and ligation steps can be carried out in a one-pot fashion, thereby simplifying the overall protocol (Scheme 6.222) [397]. This procedure eliminates the need to handle organic azides, as they are generated in situ. Other applications of microwave-assisted copper(I)-catalyzed azide-alkyne ligations ( click chemistry ) have been reported [398],... 

Sharpless, K. B. Manetsch, R. In situ click chemistry A powerful means for lead discovery. Expert Opin. Drug Discov. 2006,1, 525-538. 

Inhibition can be reversible when it simply complexes at the active site preventing further catalysis. The active enzyme under these conditions can be recovered by dialysis. Another form of inhibition is the irreversible type where the active enzyme cannot be recovered by dialysis. A variant of this type of inhibition is suicide inhibition a substrate of the enzyme reacts at the active site to yield an irreversible inhibitor which then reacts directly with groups at the active site [18]. A technique, in situ click chemistry , is related to that of suicide inhibition and involves click chemistry components which complex at the active site of an enzyme and combine to form femtomolar inhibitors. The technique can be used to synthesise inhibitors or by selection from a library of click chemistry components to search structure space of the inhibitor for the drug target [ 19]. 

Figure 7.3 Schematic representation of target-tempiated in situ Click chemistry.

Like DCC, applying in situ Click chemistry against drug discovery targets necessitates the identification of the best binding ligands. The experimental reaction mixture for in situ Click chemistry shares many component attributes in common with DCC, namely... 

Scheme 7.6 Binary azide-acetylene fragment combinations with 98 potential triazole products (including the syn- and anti-triazole regioisomers) for targeting AChE with in situ Click chemistry.

It was clear from this early work that mass spectrometric analysis would be the most appropriate technique to detect hit compounds for in situ Click chemistry applications. Although the DIOS-MS method was able to directly detect the low quantity of triazole product conversion in the presence of large amounts of protein and parent fragments, the sensitivity for this measurement was very low, with a poor signal-to-noise ratio. It was therefore both logical and desirable to optimize the sensitivity and selectivity of the MS... 

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