title: 3-Substituted Biquinolinium Inhibitors of AraC Family Transcriptional Activator VirF fromS. flexneriObtained Through In Situ Chemical Ionization of 3,4-Disubstituted Dihydroquinolines.
abstract: During a structure-activity relationship optimization campaign to develop an inhibitor of AraC family transcriptional activators, we discovered an unexpected transformation of a previously reported inhibitor that occurs under the assay conditions. Once placed in the assay media, the 3, 4-disubstituted dihydroquinoline core of the active analogue rapidly undergoes a decomposition reaction to a quaternary 3-substituted biquinolinium. Further examination established an SAR for this chemotype while also demonstrating its resilience to irreversible binding of biologically relevant nucleophiles.
authors.affiliation: Center for Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence, Kansas, 66047, USA.
authors.forename: Prashi
authors.initials: P
authors.lastname: Jain
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
authors.forename: Jiaqin
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence, Kansas, 66047, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Porubsky
authors.affiliation: Specialized Chemistry Center, The University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neuenswander
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Egan
authors.affiliation: Center for Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence, Kansas, 66047, USA ; Specialized Chemistry Center, The University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, USA ; University of Kansas Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, 2034 Becker Drive, Lawrence, KS, USA ; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: University of Kansas Center of Biomedical Research Excellence, Center for Cancer Experimental Therapeutics, 2034 Becker Drive, Lawrence, KS, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Rogers