A STRUCTURE-ACTIVITY ANALYSIS OF ANTAGONISM OF THE GROWTH-FACTOR AND ANGIOGENIC ACTIVITY OF BASIC FIBROBLAST GROWTH-FACTOR BY SURAMIN AND RELATED POLYANIONS

The ability of a series of polysulphonated naphthylureas structurally related to suramin to inhibit basic fibroblast growth factor (bFGF) or serum-stimulated growth of endothelial cells [either large vessel, hu man umbilical vein endothelial cells (HUVEC) or microvascular, bovine adrenal capillary endothelial (BACE) cells] and angiogenesis in vivo h as been examined. The polyanions encompassed two main structural varia tions, namely the number of aromatic amide groups intervening between two terminal naphthyl rings and/or variation in the substitution patte rn of the naphthyl rings. The polyanions were either inactive (group I ) or inhibited (group II) bFGF-stimulated uptake of [H-3]methylthymidi ne by BACE cells. Group I compounds shared a common structural feature in that they were simple binaphthyl-substituted ureas. In contrast, g roup II compounds all had an extended multiple ring structure with at least two aromatic groups intervening between the two terminal naphthy l rings. Compounds with either two or four intervening groups were equ ipotent in blocking bFGF in vitro. However, compounds with two bridgin g aromatic groups were 5- to 10-fold less toxic than suramin in mice, suggesting a potential for an improved therapeutic ratio. The ability of the polyanions to block bFGF-driven endothelial cell proliferation in vitro correlated with antiangiogenic activity in vivo as shown by u se of the rat sponge angiogenesis model. These observations could subs tantially widen the anti-tumour therapeutic opportunities for this cla ss of compound.