Chemistry Blog

Strained Acetylenes for Click-Chemistry

This ACIE article caught my attention. Here, a “click-chemistry” based approach is used for in vivo labeling of glycoproteins. The strained acetylene 1 is linked to biotin to give 2. Cells that have been cultured in a way as to introduce N-azidoacetylsialic acid into glycoproteins were exposed to acetylene 2, then stained with avidin-FTIC (this is a fluorescein-labeled protein with a very high affinity for biotin). As a result, the glycoproteins at the cell surface fluoresce.

What happens chemically is a [3+2]-cycloaddition of the azido-substituted sialic acid (Sia) to the acetylene to give 3. The special thing here is the absence of copper(I), which would be cytotoxic and is normally required as a cycloaddition catalyst. Instead, the addition runs without any metals because of the strain of the eight-membered ring.

This also reminds me of Sharpless’ work for the fragment-screening of HIV-1 protease inhibitors (e.g. this ACIE article). He also used the [3+2]-cycloaddition with inhibitor fragments containing azido and acetylene groups. The fragments would effectively add in situ, i.e. inside the binding site, to form strong inhibitors. Here, the enzyme itself acts as a catalyst or template by arranging the most suitable fragments in a favourable orientation.