Angiostatic effects of suramin analogs in vitro.

Suramin analogs are polyanionic naphthylureas structurally related to suramin, an antitumor agent with a narrow therapeutic window. The angiostatic activities of suramin and 16 suramin analogs were investigated using an easily quantifiable in vitro angiogenesis system. In addition, the antiproliferative activities of the analogs were studied in four different human tumor cell lines and in porcine aortic endothelial cells. The suramin analogs encompassed two main structural variations, i.e. their molecular size, and the number and substitution pattern of the sulfonate groups. Some suramin analogs with a reduced number of sulfonate groups (NF062, NF289 and NF326) showed significant dose-dependent angiostatic and also antiproliferative activities. The disulfonate NF062 was superior to suramin in inhibiting HT29 and T47D tumor cells while demonstrating a similar angiostatic potential as suramin. Therefore, the sulfonate groups in the para position of the amino groups of the naphthyl residues of suramin seem to be of special importance. The very small disulfonates (NF108, NF109, NF499, NF500 and NF241) and the asymmetric compound NF520, one half of the suramin molecule, are inactive. Therefore, a minimal molecule size seems to be essential for the biological activity. Suramin is a rather rigid molecule. The highly flexible analogs (NF527, NF528 and NF529) are inactive. This indicates that the molecular rigidity is important for the biological activity.