title: Identification of inhibitors of heparin-growth factor interactions from combinatorial libraries of four-component condensation reactions.
abstract: Chemical libraries based on four-component condensation (4CC) reactions of isocyanides were constructed to identify compounds capable of blocking heparin binding to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The reaction products in the synthesized libraries contain heparin mimetic functional groups such as carbohydrates, sulfonates, carboxylates, and hydroxy groups. These libraries have been screened for the inhibition of heparin binding to growth factors such as VEGF and bFGF. Single point screening at 5.0 microM of the 18,720 reaction products generated 26 candidates. The IC50S of these 26 compounds were determined using HPLC-purified products and 20 of the 26 showed significant inhibition of heparin binding to VEGF and/or bFGF. Eighteen of the 20 confirmed active compounds have a linear extended structure. Structures identified in this library revealed an initial relationship of structure and activity, thus providing direction for further investigation of this type of heparin mimetic libraries.
authors.affiliation: RepliGen Corporation, Needham, MA 02494, USA. jzhang@repligen.com
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Riverst
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: A
authors.initials: A
authors.lastname: Jacobson
authors.forename: J
authors.initials: J
authors.lastname: Peyers
authors.forename: G
authors.initials: G
authors.lastname: Grundstrom
authors.forename: P
authors.initials: P
authors.lastname: Burch
authors.forename: S
authors.initials: S
authors.lastname: Hussein
authors.forename: A
authors.initials: A
authors.lastname: Marolewski
authors.forename: W
authors.initials: W
authors.lastname: Herlihy
authors.forename: J
authors.initials: J
authors.lastname: Rusche
mesh_terms: D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D003486:Cyanides / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D003486:Cyanides; D016228:Endothelial Growth Factors; D006133:Growth Substances; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005346:Fibroblast Growth Factors; D006493:Heparin