Approaching an experimental electron density model of the biologically active trans-epoxysuccinyl amide group—Substituent effects vs. crystal packing

Ming W. Shi, Scott G. Stewart, Alexandre N. Sobolev, Birger Dittrich, Tanja Schirmeister, Peter Luger, Malte Hesse, Yu Sheng Chen, Peter R. Spackman, Mark A. Spackman, Simon Grabowsky

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The trans-epoxysuccinyl amide group as a biologically active moiety in cysteine protease inhibitors such as loxistatin acid E64c has been used as a benchmark system for theoretical studies of environmental effects on the electron density of small active ingredients in relation to their biological activity. Here, the synthesis and the electronic properties of the smallest possible active site model compound are reported to close the gap between the unknown experimental electron density of trans-epoxysuccinyl amides and the well-known function of related drugs. Intramolecular substituent effects are separated from intermolecular crystal packing effects on the electron density, which allows us to predict the conditions under which an experimental electron density investigation on trans-epoxysuccinyl amides will be possible. In this context, the special importance of the carboxylic acid function in the model compound for both crystal packing and biological activity is revealed through the novel tool of model energy analysis.

Original languageEnglish
Article numbere3683
Pages (from-to)1-15
Number of pages15
JournalJournal of Physical Organic Chemistry
Issue number11
Early online date24 Jan 2017
Publication statusPublished - 1 Nov 2017


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