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.show moreshow less

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Metadaten
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
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):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International