Investigating the promiscuity of the chloramphenicol nitroreductase from Haemophilus influenzae towards the reduction of 4-nitrobenzene derivatives. Issue 9 (1st May 2019)

• Record Type: Journal Article
• Authors: Green, Keith D.; Fosso, Marina Y.; Mayhoub, Abdelrahman S.; Garneau-Tsodikova, Sylvie
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 9(2019)
• Page Start: 1127
• Page End: 1132
• Publication Date: 2019-05-01
• Subjects: AG(s) aminoglycoside(s) -- AAC aminoglycoside acetyltransferase -- AME aminoglycoside-modifying enzyme -- ANT aminoglycoside nucleotidyltransferase -- APH aminoglycoside phosphotransferase -- CAM chloramphenicol -- CAT chloramphenicol acetyltransferase -- CNR chloramphenicol nitroreductase -- CoA coenzyme A -- CPT chloramphenicol phosphotransferase -- EtOAc ethyl acetate -- Et2O diethyl ether -- LCMS liquid chromatography-mass spectrometry -- MeOH methanol -- NADP(H) β-nicotinamide-adenine dinucleotide phosphate (reduced) -- NMR nuclear magnetic resonance -- RP-HPLC reversed-phase high pressure liquid chromatography -- TLC thin-layer chromatography; Antibiotic -- Bacterial enzyme -- Chemoenzymatic deprotection -- Drug-modifying enzyme -- Nitroreduction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.02.025
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Chloramphenicol nitroreductase (CNR), a drug-modifying enzyme from Haemophilus influenzae, has been shown to be responsible for the conversion of the nitro group into an amine in the antibiotic chloramphenicol (CAM). Since CAM structurally bears a 4-nitrobenzene moiety, we explored the substrate promiscuity of CNR by investigating its nitroreduction of 4-nitrobenzyl derivatives. We tested twenty compounds containing a nitrobenzene core, two nitropyridines, one compound with a vinylogous nitro group, and two aliphatic nitro compounds. In addition, we also synthesized twenty-eight 4-nitrobenzyl derivatives with ether, ester, and thioether substituents and assessed the relative activity of CNR in their presence. We found several of these compounds to be modified by CNR, with the enzyme activity ranging from 1 to 150% when compared to CAM. This data provides insights into two areas: (i) chemoenzymatic reduction of select compounds to avoid harsh chemicals and heavy metals routinely used in reductions of nitro groups and (ii) functional groups that would aid CAM in overcoming the activity of this enzyme.