In situ click chemistry: enzyme inhibitors made to their own specifications.
The in situ click chemistry approach to lead discovery employs the biological target itself for assembling inhibitors from complementary building block reagents via irreversible connection chemistry. The present publication discusses the optimization of this target-guided strategy using acetylcholinesterase (AChE) as a test system. The application of liquid chromatography with mass spectroscopic detection in the selected ion mode for product identification greatly enhanced the sensitivity and reliability of this method. It enabled the testing of multicomponent mixtures, which may dramatically increase the in situ screening throughput. In addition to the previously reported in situ product syn-TZ2PA6, we discovered three new inhibitors, syn-TZ2PA5, syn-TA2PZ6, and syn-TA2PZ5, derived from tacrine and phenylphenanthridinium azides and acetylenes, in the reactions with Electrophorus electricus and mouse AChE. All in situ-generated compounds were extremely potent AChE inhibitors, because of the presence of multiple sites of interaction, which include the newly formed triazole nexus as a significant pharmacophore.
Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Roman
R
Manetsch
Antoni
A
Krasiński
Zoran
Z
Radić
Jessica
J
Raushel
Palmer
P
Taylor
K Barry
KB
Sharpless
Hartmuth C
HC
Kolb
D000480:Alkynes / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001386:Azides / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002853:Chromatography, Liquid; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D015195:Drug Design; D004593:Electrophorus / Q000378:metabolism; D007700:Kinetics; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D013045:Species Specificity; D014101:Torpedo / Q000378:metabolism
D000480:Alkynes; D001386:Azides; D002800:Cholinesterase Inhibitors