Strained Acetylenes for Click-Chemistry
by Phil on Feb 22 2008 (2856 Views)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.
Hi Phil,
FYI, you might also be interested in this PNAS paper from a few months ago, which also involved copper-free click chemistry…
I think it is debate-able but we’ll see.
Hi Joshua,
thanks for pointing this out. Bertozzi already published a JACS paper about strain-promoted cycloaddition in 2004. In the ACIE paper they claim that the reaction rate is increased by the greater ring strain caused by the benzene rings, and by the electron withdrawal due to conjugation.
hi,
iam working on immobilizing dna on the slide using copper free click chemistry, so does anyone know if the compound 1 mentioned above is commercially available?? can you please mail me if you know any info about this my id is vamsi_bangalore@rediffmail.com
thank you,
vamsee.
Click Chemistry…..Zzzzzzzzzzz. I think the problem is most people were over it before Sharpless was…
Hi,
Several compounds similar to 1 for copper free chemistry are commercially avaliable @ clickchemistrytools.com
A direct improvement showed up lately: Journal of the American Chemical Society, 2010, DOI 10.1021/ja100014q
Briefly described as “BARAC – yet another strain-promoted copper-free click chemistry” http://clickchemistry.blogspot.com/2010/03/barac-yet-another-strain-promoted.html