Phenylphthalimides with Tumor Necrosis Factor Alpha Production-Enhancing Activity

Abstract

Phenylphthalimides (2-phenyl-1H-isoindole-1, 3-diones) were prepared and their effects on tumor necrosis factor alpha (TNF-α) 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-α 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-α production to more than 600% at the concentration of 1×10^-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-α production to more than 800% and 700%, respectively, at the concentration of 1×10^-5 M. Introduction of fluorines into the phthalimide moiety of PP-33 greatly lowered the concentration of the compound necessary to elicit the TNF-α production-enhancing activity;2-(2, 6-diisopropylphenyl)-4, 5, 6, 7-tetrafluoro-1H-isoindole-1, 3-dione (FPP-33) showed the activity at nanomolar concentration, with the optimum concentration of 1×10^-7 M.