Synthesis and binding mode of heterocyclic analogues of suramin inhibiting the human basic fibroblast growth factor.
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.
Manetti
F
F
Dipartimento Farmaco Chimico Tecnologico, Universita' degli Studi di Siena, Italy.
Cappello
V
V
Botta
M
M
Corelli
F
F
Mongelli
N
N
Biasoli
G
G
Borgia
A L
AL
Ciomei
M
M
D016475:3T3 Cells; D000482:Allantois / Q000098:blood supply / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013498:Suramin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D008024:Ligands; D009281:Naphthalenes; D011720:Pyrazoles; D011758:Pyrroles; C115096:bis(8(4-(4-amino-1-methyl-1H-pyrrole-2-carbonylamino)-1-methyl-1H-pyrrole-2-carbonylamino)naphthalene-1,5-disulfonic acid) tetrasodium salt; D016222:Fibroblast Growth Factor 2; D013498:Suramin