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Most Requested Journal Articles 4Q04-Chemistry and Related Science

Following is one of the journal articles most requested by researchers using CAS online services.

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CAS indexed 11 chemical substances from this document. CAS subject entries for this document include: Free energy of binding; Enzyme kinetics.

CAPLUS COPYRIGHT 2005 ACS on STN

TITLE:	In Situ Click Chemistry: Enzyme Inhibitors Made to Their Own Specifications
AUTHOR(S):	Manetsch, Roman; Krasinski, Antoni; Radic, Zoran; Raushel, Jessica; Taylor, Palmer; Sharpless, K. Barry; Kolb, Hartmuth C.
CORPORATE SOURCE:	Department of Chemistry and the Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA, 92037, USA
SOURCE:	Journal of the American Chemical Society (2004), 126(40), 12809-12818 CODEN: JACSAT; ISSN: 0002-7863
PUBLISHER:	American Chemical Society
LANGUAGE:	English

ABSTRACT:
The in situ click chem. approach to lead discovery employs the biol. target itself for assembling inhibitors from complementary building block reagents via irreversible connection chem. The present publication discusses the optimization of this target-guided strategy using acetylcholinesterase (AChE) as a test system. The application of liq. chromatog. 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 mixts., which may dramatically increase the in situ screening throughput. In addn. to the previously reported in situ product syn-TZ2PA6, the authors 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 compds. 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. Safety issues in handling the potentially neurotoxic inhibitors are also discussed.

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