4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor kappa B activation

1 The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylb enzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the activation of NF-kappa B elicited by tumour necrosis factor-alpha (T NF-alpha) on human umbilical vein endothelial cells (HUVEC) was tested. 2 The expression of the mRNA of vascular cell adhesion molecule-1 (VCAM-1) was studied as an example of a gene the expression of which is regulated by NF-kappa B. To extend these findings to other systems, the induction of ni tric oxide synthase in rat adherent peritoneal macrophages was studied. 3 Both HTB and triflusal were more potent than aspirin or salicylate as inh ibitors of the nuclear translocation of NF-kappa B. The calculation of the IC50 values showed approximate to 2 mM for HTB, 4 mM for aspirin and >4 mM for salicylate. 4 Comparison of the potency of these compounds on VCAM-1 mRNA expression sh owed complete inhibition by both triflusal and HTB at a concentration of 4 mM whereas aspirin and salicylate produced only 36-43% inhibition at the sa me concentration. 5 Inhibition of NF-kappa B activation was also observed in rat peritoneal m acrophages stimulated via their receptors for the Fc portion of the antibod y molecule with IgG/ovalbumin immune complexes. This was accompanied by a d ose-dependent inhibition of nitrite production by the L-arginine pathway vi a iNOS. IC50 values for this effect were 1.13+/-0.12 mM (triflusal), 1.84+/ -0.34 (HTB), 6.08 +/- 1.53 mM (aspirin) and 9.16 +/- 1.9 mM (salicylate). 6 These data indicate that the incorporation of a 4-trifluoromethyl group t o the salicylate molecule strongly enhances its inhibitory effect on NF-kap pa B activation, VCAM-1 mRNA expression and iNOS induction, irrespective of the presence of the acetyl moiety involved in the inhibition of cyclooxyge nase.