Phenylphthalimides with tumor necrosis factor alpha production-enhancing activity.
Phenylphthalimides (2-phenyl-1H-isoindole-1,3-diones) were prepared and their effects on tumor necrosis factor alpha (TNF-alpha) production by human leukemia cell line HL-60 stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined. An analysis of the structure-activity relationships of the phenylphthalimides indicated that potent enhancing activity on TPA-induced TNF-alpha production by HL-60 cells requires medium-sized substituent(s) at the ortho position(s) of the phenyl group; 2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (PP-33) increased the TNF-alpha production to more than 600% at the concentration of 1 x 10(-5) M. Introduction of a nitro group at the phthalimide moiety of PP-33 enhanced the activity; 2-(2,6-diisopropylphenyl)-4-nitro-1H-isoindole-1,3-dione (4NPP-33) and its 5-nitro isomer (5NPP-33) enhanced the TNF-alpha production to more than 800% and 700%, respectively, at the concentration of 1 x 10(-5) M. Introduction of fluorines into the phthalimide moiety of PP-33 greatly lowered the concentration of the compound necessary to elicit the TNF-alpha production-enhancing activity; 2-(2,6-diisopropylphenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3-dio ne (FPP-33) showed the activity at nanomolar concentration, with the optimum concentration of 1 x 10(-7) M.
Shibata
Y
Y
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Sasaki
K
K
Hashimoto
Y
Y
Iwasaki
S
S
D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010797:Phthalimides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D010797:Phthalimides; D014409:Tumor Necrosis Factor-alpha; C037430:N-phenylphthalimide