Shibata Y, Sasaki K, Hashimoto Y, Iwasaki S
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Chem Pharm Bull (Tokyo). 1996 Jan;44(1):156-62. doi: 10.1248/cpb.44.156.
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.
