title: Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate.
abstract: Inhibition of angiogenesis-promoting factors such as fibroblast growth factors is considered to be a potential procedure for inhibiting solid tumor growth. Although several peptide-based inhibitors are currently under study, the development of antiangiogenic compounds of small molecular size is a pharmacological goal of considerable interest. We have already shown that certain naphthalene sulfonates constitute minimal functional substitutes of the antiangiogenic compounds of the suramin and suradista family. Using those data as a lead, we have carried out a rational search for new angiogenesis inhibitors that could provide new pharmacological insights for the development of antiangiogenic treatments. The results of the study strongly underline the relevance of the stereochemistry for an efficient inhibition of acidic fibroblast growth factor mitogenic activity by the naphthalene sulfonate family and allow us to formulate rules to aid in searching for new inhibitors and pharmaceutical developments. To provide further leads for such developments and acquire a detailed insight into the basis of the inhibitory activity of the naphthalene sulfonate derivatives, we solved the three-dimensional structure of acidic fibroblast growth factor complexed to 5-amino-2-naphthalenesulfonate, the most pharmacologically promising of the identified inhibitors. The structure shows that binding of this compound would hamper the interaction of acidic fibroblast growth factor with the different components of the cell membrane mitogenesis-triggering complex.
authors.affiliation: Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, C/Velázquez 144, 28006 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Tornero
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Lozano
authors.forename: Mariano
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gómez
authors.forename: José C
authors.initials: JC
authors.lastname: López
authors.forename: Ernesto
authors.initials: E
authors.lastname: Quesada
authors.forename: Clara
authors.initials: C
authors.lastname: Uriel
authors.forename: Serafín
authors.initials: S
authors.lastname: Valverde
authors.forename: Pedro
authors.initials: P
authors.lastname: Cuevas
authors.forename: Antonio
authors.initials: A
authors.lastname: Romero
authors.forename: Guillermo
authors.initials: G
authors.lastname: Giménez-Gallego
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry* / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009282:Naphthalenesulfonates / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D012964:Sodium / Q000494:pharmacology
chemical_list: C475668:5-amino-2-naphthalenesulfonate; D020533:Angiogenesis Inhibitors; D009282:Naphthalenesulfonates; D016220:Fibroblast Growth Factor 1; D006493:Heparin; D012964:Sodium