Naphthoquinones as covalent reversible inhibitors of cysteine proteases — studies on inhibition mechanism and kinetics
Please always quote using this URN: urn:nbn:de:bvb:20-opus-203791
- The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid.The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.…
Author: | Philipp Klein, Fabian Barthels, Patrick Johe, Annika Wagner, Stefan Tenzer, Ute Distler, Thien Anh Le, Paul Schmid, Volker Engel, Bernd Engels, Ute A. Hellmich, Till Opatz, Tanja Schirmeister |
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URN: | urn:nbn:de:bvb:20-opus-203791 |
Document Type: | Journal article |
Faculties: | Fakultät für Chemie und Pharmazie / Institut für Physikalische und Theoretische Chemie |
Language: | English |
Parent Title (English): | Molecules |
ISSN: | 1420-3049 |
Year of Completion: | 2020 |
Volume: | 25 |
Issue: | 9 |
Article Number: | 2064 |
Source: | Molecules (2020) 25:9, 2064. https://doi.org/10.3390/molecules25092064 |
DOI: | https://doi.org/10.3390/molecules25092064 |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Tag: | 1,4-naphthoquinone; covalent reversible inhibition; nucleophilic addition; prodrug; protease; rhodesain |
Release Date: | 2022/06/01 |
Date of first Publication: | 2020/04/28 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |