TY - JOUR
T1 - Oxidative Reactivities of 2-Furylquinolines
T2 - Ubiquitous Scaffolds in Common High-Throughput Screening Libraries
AU - Olson, Margaret E.
AU - Abate-Pella, Daniel
AU - Perkins, Angela L.
AU - Li, Ming
AU - Carpenter, Michael A.
AU - Rathore, Anurag
AU - Harris, Reuben S.
AU - Harki, Daniel A.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/9/24
Y1 - 2015/9/24
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.5b00930
DO - 10.1021/acs.jmedchem.5b00930
M3 - Article
C2 - 26358009
AN - SCOPUS:84942280010
SN - 0022-2623
VL - 58
SP - 7419
EP - 7430
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 18
ER -