An Unexpected Example of Protein-Templated Click Chemistry

✍ Scribed by Dr. Takayoshi Suzuki; Yosuke Ota; Yuki Kasuya; Dr. Motoh Mutsuga; Dr. Yoko Kawamura; Dr. Hiroki Tsumoto; Dr. Hidehiko Nakagawa; Prof. M. G. Finn; Prof. Naoki Miyata

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 360 KB
• Volume: 49
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/anie.201002205

✦ Synopsis

Click chemistry is a popular approach to the synthesis of functionalized molecules, and emphasizes the use of practical and reliable reactions. [1] Copper(I)-catalyzed azide-alkyne cycloaddition [2] (CuAAC), which selectively produces anti-(1,4)-triazoles in preference to the syn isomer (1,5-triazole), is regarded as a superlative example of click chemistry. The CuAAC reaction can be accelerated by Cu I -stabilizing ligands, such as tris[(1-substituted-1H-1,2,3-triazol-4-yl)methyl]amines [3] and tris(2-benzimidazolylmethyl)amines. [4] The catalytic system has received a great deal of use in various fields such as chemical biology and materials science. [1,5] The 1,3-dipolar cycloaddition of azides with unactivated alkynes occurs much more slowly but is highly chemoselective. This property stimulated the development of "in situ click chemistry" for the field of drug discovery, in which target enzymes are allowed to assemble new inhibitors by linking azides and alkynes that bind to adjacent sites on the protein surface. [6] The linkage reaction does not employ Cu catalysis, but instead relies on acceleration of the otherwise sluggish [3+2] cycloaddition reaction when the reaction partners are held in proximity to each other, often in or near the enzyme active site. In the course of an in situ click chemistry study on histone deacetylase (HDAC), we unexpectedly observed acceleration of the AAC reaction by trace copper associated with the protein in a structurally sensitive manner. Herein we report these findings, which constitute the first example of a Cu-protein complex catalyzing the AAC reaction.

HDAC inhibitors are attractive drug candidates for cancer, inflammation, and neurodegenerative disorders.