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

Abstract

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.

Authors:
 [1];  [1];  [1];  [2];  [3];  [4];  [5];  [6];  [1];  [1]; ORCiD logo [7]
  1. School of Chemistry and Biochemistry, The University of Western Australia, Perth WA Australia
  2. Anorganische Chemie und Strukturchemie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf Germany
  3. Institut für Pharmazie und Biochemie, Johannes-Gutenberg-Universität Mainz, Mainz Germany
  4. Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin, Berlin Germany
  5. Fachbereich 2-Biologie/Chemie, Institut für Anorganische Chemie und Kristallographie, Universität Bremen, Bremen Germany
  6. ChemMatCARS, The University of Chicago, Argonne IL USA
  7. School of Chemistry and Biochemistry, The University of Western Australia, Perth WA Australia; Fachbereich 2-Biologie/Chemie, Institut für Anorganische Chemie und Kristallographie, Universität Bremen, Bremen Germany
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGN
OSTI Identifier:
1406635
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Physical Organic Chemistry; Journal Volume: 30; Journal Issue: 11
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Shi, Ming W., Stewart, Scott G., Sobolev, Alexandre N., Dittrich, Birger, Schirmeister, Tanja, Luger, Peter, Hesse, Malte, Chen, Yu-Sheng, Spackman, Peter R., Spackman, Mark A., and Grabowsky, Simon. Approaching an experimental electron density model of the biologically active trans -epoxysuccinyl amide group-Substituent effects vs. crystal packing. United States: N. p., 2017. Web. doi:10.1002/poc.3683.
Shi, Ming W., Stewart, Scott G., Sobolev, Alexandre N., Dittrich, Birger, Schirmeister, Tanja, Luger, Peter, Hesse, Malte, Chen, Yu-Sheng, Spackman, Peter R., Spackman, Mark A., & Grabowsky, Simon. Approaching an experimental electron density model of the biologically active trans -epoxysuccinyl amide group-Substituent effects vs. crystal packing. United States. doi:10.1002/poc.3683.
Shi, Ming W., Stewart, Scott G., Sobolev, Alexandre N., Dittrich, Birger, Schirmeister, Tanja, Luger, Peter, Hesse, Malte, Chen, Yu-Sheng, Spackman, Peter R., Spackman, Mark A., and Grabowsky, Simon. Tue . "Approaching an experimental electron density model of the biologically active trans -epoxysuccinyl amide group-Substituent effects vs. crystal packing". United States. doi:10.1002/poc.3683.
@article{osti_1406635,
title = {Approaching an experimental electron density model of the biologically active trans -epoxysuccinyl amide group-Substituent effects vs. crystal packing},
author = {Shi, Ming W. and Stewart, Scott G. and Sobolev, Alexandre N. and Dittrich, Birger and Schirmeister, Tanja and Luger, Peter and Hesse, Malte and Chen, Yu-Sheng and Spackman, Peter R. and Spackman, Mark A. and Grabowsky, Simon},
abstractNote = {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.},
doi = {10.1002/poc.3683},
journal = {Journal of Physical Organic Chemistry},
number = 11,
volume = 30,
place = {United States},
year = {Tue Jan 24 00:00:00 EST 2017},
month = {Tue Jan 24 00:00:00 EST 2017}
}
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