Benzylphthalimides and phenethylphthalimides with thalidomide-like activity on the production of tumor necrosis factor alpha.
Benzylphthalimide analogs (P1P's) and phenethylphthalimide analogs (P2P's) have been found to exhibit thalidomide-like activity on the production of tumor necrosis factor (TNF)-alpha by the human leukemia cell line, HL-60, stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA). Structure-activity relationships are discussed on the basis of the TNF-alpha production-enhancing activity. Benzylphthalimide (P1P-00) exhibited which is weaker than that of thalidomide, but introduction of a methyl group at the ortho-position of the benzyl moiety (P1P-10) resulted an increase to a level comparable with that of thalidomide. Phenethylphthalimide (P2P-00) is more potent than thalidomide, and its fluorinated derivative, 2-phenethyl-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione (FP2P-00), exhibited potent activity at very low concentrations.
Sasaki
K
K
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Shibata
Y
Y
Hashimoto
Y
Y
Iwasaki
S
S
D018922:HL-60 Cells; D006801:Humans; D010797:Phthalimides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D010797:Phthalimides; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D013755:Tetradecanoylphorbol Acetate