Abstract:
:The design, synthesis, and biological evaluation of a series of pyrrole and pyrazole congeners 2 of suramin, directed toward the development and identification of new ligands that complex the human fibroblast growth factor (bFGF), thereby inhibiting tumor-promoted angiogenesis, is reported. Compounds 2 were evaluated for their ability to inhibit binding of bFGF to its receptor, in vivo bFGF-induced angiogenesis, and neovascularization of the chorioallantoic membrane in comparison with suramin. These assays showed that ligands 2 exhibit moderate to good activity, comparable to that of suramin, and are less toxic than suramin itself. In this study, affinity data of ligands in combination with the crystal structure of bFGF were used to explain structure-affinity relationships and to gain an insight into the possible mode of ligand-protein interaction. Due to the lack of experimental structural data on the ligand-bFGF complexes, molecular mechanics techniques were used to obtain putative bioactive conformations and to generate docked complexes with the three-dimensional structure of bFGF. These experiments led to suggest that compounds 2 give rise to 1:1 complexes with bFGF through an unprecedented, bidentate attachment of their naphthylsulfonate groups to two main domains, commonly referred to as the heparin binding site and the receptor binding site, on bFGF, thus preventing the interaction of the growth factor with its receptor.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Manetti F,Cappello V,Botta M,Corelli F,Mongelli N,Biasoli G,Borgia AL,Ciomei Mdoi
10.1016/s0968-0896(98)00052-2subject
Has Abstractpub_date
1998-07-01 00:00:00pages
947-58issue
7eissn
0968-0896issn
1464-3391pii
S0968089698000522journal_volume
6pub_type
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