New sulfonated distamycin A derivatives with bFGF complexing activity.
Tumor-induced neoangiogenesis is an essential event for solid tumor growth. Therefore, a compound able to block angiogenesis-promoting factors could have antitumor activity. The polysulfonated naphthylurea suramin is hypothesized to have this mode of action. A series of sulfonated 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 chorioallantoic membrane, in comparison with suramin. The two most active compounds, FCE 26644 [7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-met hyl-4,2- pyrrole)carbonylimino))-bis(1,3-naphthalenedisulfonic acid)] and FCE 27164 [7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino(N-met hyl-4,2- pyrrole) carbonylimino)-bis (1,3,5-naphthalenetrisulfonic acid)] have been selected for extended evaluation. Both compounds are active in inhibiting platelet-derived growth factor beta (PDGF beta) and interleukin-1 beta binding. Two different assays have been performed to study their mode of action: the sequential binding assay on bFGF and PDGF receptors and the bFGF-induced tyrosine phosphorylation assay. The results of the two assays are in agreement and indicate that no activity is observed if FCE 26644, FCE 27164 and suramin are administered as pretreatment, when a direct interaction of the compounds 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.
Ciomei
M
M
Farmitalia Carlo Erba, Research Center, Experimental Oncology Laboratory, Milano, Italy.
Pastori
W
W
Mariani
M
M
Sola
F
F
Grandi
M
M
Mongelli
N
N
D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive; D004214:Distamycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000494:pharmacology*; D013498:Suramin / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
D004214:Distamycins; C085720:FCE 26644; D013451:Sulfonic Acids; D016222:Fibroblast Growth Factor 2; C085721:FCE 27164; D014443:Tyrosine; D013498:Suramin; C030000:stallimycin