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

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 (2017). Approaching an experimental electron density model of the biologically active trans-epoxysuccinyl amide group-Substituent effects vs. crystal packing. Journal of physical organic chemistry, 30(11), e3683. Wiley 10.1002/poc.3683

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Grabowsky, Simon

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0894-3230

Publisher:

Wiley

Language:

English

Submitter:

Simon Grabowsky

Date Deposited:

06 Feb 2020 11:35

Last Modified:

09 Feb 2020 02:45

Publisher DOI:

10.1002/poc.3683

BORIS DOI:

10.7892/boris.138442

URI:

https://boris.unibe.ch/id/eprint/138442

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