Mono- or Di-fluorinated analogues of flavone-8-acetic acid:: Synthesis and in vitro biological activity

Background: Previously, the antitumour activity of some flavone-8-acetic acid (FAA) derivatives substituted with an acid function in position 2 of the benzene ring was evaluated. The most active compound resulted the one bearing a fluorine atom in position 7 of the flavone nucleus. In this paper, we evaluated new mono- or di-fluorinated FAA derivatives. Materials and Methods: The cytotoxicity towards two human ovarian adenocarcinoma cell lines, the capability to stimulate human mononuclear cells and murine macrophages' lytic properties were evaluated by MTT. Moreover, the potentiation of lipopolysaccharide (LPS) activity was studied by ELISA analysis of TNF-alpha release. Results: The analogues showed a direct cytotoxicity comparable to that of 5,6-dimethyl-xanthen-9-one-4-acetic acid (DMXAA), at present in clinical trials. None of the tested compounds was able to stimulate human mononuclear cells' lytic properties after either 4- or 24-h treatment, while after 4-h treatment, the derivative 5a was more able to stimulate murine macrophages with respect to DMXAA. Moreover, a significant increase of 5c and 5d activation was obtained with LPS association, reflected by TNF-alpha production as well. Conclusion: Like FAA, the new fluorinated derivatives 5a, 5c and 5d showed remarkable activity in murine cells, but this was not confirmed in human models.