title: Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries.
abstract: High-throughput screening (HTS) was employed to discover APOBEC3G inhibitors, and multiple 2-furylquinolines (e.g., 1) were found. Dose-response assays with 1 from the HTS sample, as well as commercial material, yielded similar confirmatory results. Interestingly, freshly synthesized and DMSO-solubilized 1 was inactive. Repeated screening of the DMSO aliquot of synthesized 1 revealed increasing APOBEC3G inhibitory activity with age, suggesting that 1 decomposes into an active inhibitor. Laboratory aging of 1 followed by analysis revealed that 1 undergoes oxidative decomposition in air, resulting from a [4 + 2] cycloaddition between the furan of 1 and (1)O2. The resulting endoperoxide then undergoes additional transformations, highlighted by Baeyer-Villager rearrangements, to deliver lactam, carboxylic acid, and aldehyde products. The endoperoxide also undergoes hydrolytic opening followed by further transformations to a bis-enone. Eight structurally related analogues from HTS libraries were similarly reactive. This study constitutes a cautionary tale to validate 2-furylquinolines for structure and stability prior to chemical optimization campaigns.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Olson
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abate-Pella
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Perkins
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carpenter
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Anurag
authors.initials: A
authors.lastname: Rathore
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biochemistry, Molecular Biology & Biophysics, and §Masonic Cancer Center, University of Minnesota , 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Harki
mesh_terms: D000071480:APOBEC-3G Deaminase; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005663:Furans / Q000737:chemistry*; D057809:HEK293 Cells; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D010084:Oxidation-Reduction; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries; D012996:Solutions; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D005663:Furans; D011804:Quinolines; D054852:Small Molecule Libraries; D012996:Solutions; D013830:Thiadiazoles; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; D004121:Dimethyl Sulfoxide