Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid proteases

Jian Yang; Marta Barniol-Xicota; Minh T N Nguyen; Anezka Ticha; Kvido Strisovsky; Steven H L Verhelst

doi:10.1016/j.bmcl.2017.12.056

Benzoxazin-4-ones as novel, easily accessible inhibitors for rhomboid proteases

Bioorg Med Chem Lett. 2018 May 1;28(8):1423-1427. doi: 10.1016/j.bmcl.2017.12.056. Epub 2017 Dec 26.

Authors

Jian Yang¹, Marta Barniol-Xicota¹, Minh T N Nguyen², Anezka Ticha³, Kvido Strisovsky³, Steven H L Verhelst⁴

Affiliations

¹ KU Leuven - University of Leuven, Laboratory of Chemical Biology, Department of Cellular & Molecular Medicine, Herestraat 49 Box 802, 3000 Leuven, Belgium.
² Leibniz Institute for Analytical Sciences ISAS, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany.
³ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, Prague 166 10, Czech Republic.
⁴ KU Leuven - University of Leuven, Laboratory of Chemical Biology, Department of Cellular & Molecular Medicine, Herestraat 49 Box 802, 3000 Leuven, Belgium; Leibniz Institute for Analytical Sciences ISAS, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany. Electronic address: [email protected].

PMID: 29506958
DOI: 10.1016/j.bmcl.2017.12.056

Abstract

Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.

Keywords: Activity-based protein profiling; Benzoxazinones; Inhibitors; Intramembrane proteases; Rhomboid proteases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacillus subtilis / enzymology
Benzoxazines / chemical synthesis
Benzoxazines / chemistry
Benzoxazines / pharmacology*
Cattle
Chymotrypsin / antagonists & inhibitors
DNA-Binding Proteins / antagonists & inhibitors*
Endopeptidases
Enzyme Assays
Escherichia coli / enzymology
Escherichia coli Proteins / antagonists & inhibitors*
Membrane Proteins / antagonists & inhibitors*
Molecular Structure
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship
Trypsin / chemistry
Trypsin Inhibitors / chemical synthesis
Trypsin Inhibitors / chemistry
Trypsin Inhibitors / pharmacology
ortho-Aminobenzoates / chemistry

Substances

Benzoxazines
DNA-Binding Proteins
Escherichia coli Proteins
GlpG protein, E coli
Membrane Proteins
Serine Proteinase Inhibitors
Trypsin Inhibitors
ortho-Aminobenzoates
Endopeptidases
Chymotrypsin
Trypsin