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 1O2. 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.
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© 2015 American Chemical Society.