NEW SULFONATED DISTAMYCIN-A DERIVATIVES WITH BFGF COMPLEXING ACTIVITY

Tumor-induced neoangiogenesis is an essential event for solid tumor gr owth. Therefore, a compound able to block angiogenesis-promoting facto rs could have antitumor activity. The polysulfonated naphthylurea sura min is hypothesized to have this mode of action. A series of sulfonate d distamycin A derivatives have been synthesized with the objective of identifying novel compounds able to complex basic fibroblastic growth factor (bFGF) and other factors involved in tumour angiogenesis, and consequently to block the angiogenic process. These new compounds have been characterized for their ability to inhibit bFGF binding, in vivo bFGF-induced angiogenesis and neovascularization of the chorioallanto ic membrane, in comparison with suramin. The two most active compounds , FCE 26644 [7,7'-(carbonyl- bis(imino-N-methyl-4,2-pyrrolecarbonyl- i mino(N-methyl-4,2-pyrrole)carbonylimino))- bis(1,3-naphthalenedisulfon ic acid)] and FCE 27164 bonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-i mino (N-methyl-4,2-pyrrole) carbonylimino)-bis (1,3,5-naphthalenetrisu lfonic acid)] have have been selected for extended evaluation. Both co mpounds are active in inhibiting platelet-derived growth factor beta ( PDGF beta) and interleukin-1 beta binding. Two different assays have b een performed to study their mode of action: the sequential binding as say on bFGF and PDGF receptors and the bFGF-induced tyrosine phosphory lation assay. The results of the two assays are in agreement and indic ate that no activity is observed if FCE 26644, FCE 27164 and suramin a re administered as pretreatment, when a direct interaction of the comp ounds with bFGF and PDGF receptors is required. Conversely, inhibitory activity is observed when the compounds are allowed to form complexes with the growth factors themselves.