Enhanced potency of perfluorinated thalidomide derivatives for inhibition of LPS-induced tumor necrosis factor-alpha production is associated with a change of mechanism of action.
Perfluorination of phthalimides leads to dramatically increased potency as inhibitors of TNF-alpha production. We examined the enantiodependence for several tetrafluorophthalimides and alpha-methylthalidomide, 3. Only 3 exhibited strikingly enantiodependent activity. The key structural determinant for the enhanced activity is the tetrafluorophthaloyl group, which confers enhanced potency and a change in the mechanism of inhibition.
Niwayama
S
S
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139, USA.
Loh
C
C
Turk
B E
BE
Liu
J O
JO
Miyachi
H
H
Hashimoto
Y
Y
D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C100913:tetrafluorothalidomide; D013792:Thalidomide