related to degree

• Raushel, Jessica, Ph.D. in Chemistry, Scripps Research 2003 - 2008

authors

• Manetsch, R.
• Krasinski, A.
• Radic, Z.
• Raushel, Jessica
• Taylor, P.
• Sharpless, K. Barry
• Kolb, H. C.

publication date

• 2004

journal

• Journal of the American Chemical Society  Journal

abstract

• 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.

subject areas

• Alkynes
• Animals
• Azides
• Cholinesterase Inhibitors
• Chromatography, Liquid
• Combinatorial Chemistry Techniques
• Drug Design
• Electrophorus
• Kinetics
• Mass Spectrometry
• Mice
• Models, Molecular
• Species Specificity
• Torpedo

International Standard Serial Number (ISSN)

• 0002-7863

Digital Object Identifier (DOI)

• 10.1021/ja046382g

PubMed ID

• 15469276

start page

• 12809

end page

• 12818

volume

• 126

issue

• 40