| STUDY |
So far, the fittest click chemistry reaction is the Huisgen 1,3-dipolar cycloaddition of alkynes and azides to form triazoles, Sharpless said. "It is not used much, even though it goes downhill by about 50 kcal per mole." He described how he has used this chemistry to let enzymes reveal their "deepest, darkest secrets"--that is, to let "enzymes discover their own best inhibitors." Proof of principle was established with acetylcholinesterases, which are involved in neurotransmission. The enzyme's active site is located at the bottom of a deep gorge. Known inhibitors bind either to the active site or to a secondary site, the rim of the gorge. Those that bind the active site have long been used to treat Alzheimer's dementia. Sharpless and coworkers used acetylcholinesterase as a reaction vessel for the triazole-forming reaction. The reactants consisted of dozens of azides and acetylenes attached to building blocks made up of known inhibitors that are selective for either the enzyme's active site or the secondary site. The hope was that click chemistry occurring within the enzyme would produce more potent and more selective inhibitors, binding both the active and the secondary sites. The cycloaddition reaction between azides and acetylenes usually yields a 1:1 mixture of syn and anti triazoles. It is very slow at room temperature, but in certain cases it is dramatically accelerated by acetylcholinesterase. By using the enzyme's active site as a template, Sharpless and coworkers found one pair of building blocks that form the most potent noncovalent inhibitors of acetylcholinesterase to date. Furthermore, the enzyme-mediated reaction gives only the syn product, which binds the enzyme more strongly than does the anti product |
| UPDATE | 02.04 |
| AUTHOR | Scripps s Sharpless et al |
| LITERATURE REF. | Angew. Chem. Int. Ed., 41, 1053 (2002) |
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