Clickables: a small molecule library for click chemistry

"Click chemistry" is a term introduced by Barry Sharpless to describe high yielding, "easy" chemical reactions. Although there are several potential click reactions, the Copper(I) catalyzed synthesis of triazoles from azides and acetylenes has become synonymous with the term click chemistry.
The Cutler lab has assembled a collection of ~2800 drug-like terminal acetylene small molecules from a variety of vendors. Hits from this library can be used directly in downstream click chemistry reactions. Additionally, library compounds can be clicked against azide building blocks to create new libraries with tailored properties.
We have been funded by the IIGB to use the Clickables to synthesize libraries where all members possess an amine functional group and one of several different fluorophores. The amine handle enables affinity resin synthesis and target identification via reaction with activated carboxylic acid affinity resins (i.e. Affigel) and the fluorophore enables visualization of hits in living cells or other contexts.

Updates
April 2009: ~1300 new terminal acetylenes purchased from Enamine. The "clickables" terminal acetylene library now contains over 4000 clickable small molecules.
March 2009: Andrew Defries has taken over the project and is in the midst of synthesizing and screening libraries made from the 8 building blocks shown below. Our target library of 8 tags clicked against 2760 acetylenes (~22K compounds) should be complete by April 2009. The first library synthesis and screen (DEAC tag) enabled us to work out a few kinks in the methodology and hit followup process, which is now running smoothly. We have isolated some compounds producing nice phenotypes and when the screens are completed we will select compounds for preparation of affinity reagents.
August 2008: The first ~2800 member tagged / fluorescent library has been synthesized using the diethylcoumarin (DEAC) building block shown at left (thank you IIGB for financial support of this pilot project!). We have found that the majority of acetylenes in the library (~70%) work extremely well when clicked against our DEAC probe (i.e. 100% dye consumption in the reactions). A pilot screen of 1040 fluorescently tagged compounds for bioactivity in Arabidopsis etiolated seedlings will be completed in the next week. We are screening for cell expansion inhibitors in etiolated Arabidopsis seedlings and also looking for enhancers of three herbicides (screened at sub-phenotype inducing concentrations). Details will be posted as available. We are sharing the tagged libraries with UCR CEPCEB members and anyone else with an interest in screening them. Contact Sean for more information.

If you are interested in obtaining an aliquot of the Clickables or our tagged libraries, contact Sean.

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