10.1021/jm101623p.s001
Stefanie Bühler
Stefanie
Bühler
Marcia Goettert
Marcia
Goettert
Dieter Schollmeyer
Dieter
Schollmeyer
Wolfgang Albrecht
Wolfgang
Albrecht
Stefan A. Laufer
Stefan A.
Laufer
Chiral Sulfoxides as Metabolites of 2-Thioimidazole-Based p38α Mitogen-Activated Protein Kinase Inhibitors: Enantioselective Synthesis and Biological Evaluation
American Chemical Society
2011
Biological EvaluationA number
chiral sulfoxides
oxidation
HWB
IC 50
TNF
p 38α MAPK
2011-05-12 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Chiral_Sulfoxides_as_Metabolites_of_2_Thioimidazole_Based_p38_Mitogen_Activated_Protein_Kinase_Inhibitors_Enantioselective_Synthesis_and_Biological_Evaluation/2653348
A number of pharmaceutically important drugs contain asymmetric sulfinyl moieties, so the biological evaluation of chiral sulfoxides as human drug metabolites is important for the development of safe and effective pharmaceuticals. Asymmetric oxidation is one of the most attractive ways to prepare chiral sulfoxides. In combination with different chiral ligands, the iron- and titanium-catalyzed asymmetric oxidations of tri- and tetrasubstituted 2-thioimidazoles afford the corresponding sulfoxides with enantiomeric excesses up to 99% as novel p38α mitogen-activated protein kinase (p38α MAPK) inhibitors. The enantiomerically pure sulfoxides were evaluated on their inhibitory potency against p38α MAPK compared to the respective sulfides and sulfoxide racemates and showed differences in their affinities for the enzyme with IC<sub>50</sub> in the low nanomolar range. In addition, the ability to inhibit the release of tumor necrosis factor-α (TNF-α) from human whole blood (HWB) was examined. Some pyridinylimidazole derivatives showed excellent HWB activity with IC<sub>50</sub> as low as 52 nM.