Identification of novel inhibitors of fibroblast growth factor (FGF-2) binding to heparin and endothelial cell survival from a structurally diverse carbohybrid library

Murphy, Paul V.; Pitt, Nigel; O'Brien, Alan; Enright, Philomena M.; Dunne, A; Wilson, Stephen J.; Duane, Rhona M; O’Boyle, Kathy M.

doi:10.1016/s0960-894x(02)00700-x

Cited by 23 publications

(6 citation statements)

References 14 publications

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“…Apart from polyanionic polymers such as sulfated polysaccharides, [7] poly(N-acrylamino acids), [8] sulfonic acid polymers, [9] hydroxylated and carboxylated polyaromatic compounds, [10] and oligoribonucleic acids, [11] small-molecule candidates derived from dipeptides, [12] glycoconjugates, [13] suramin and its analogues, [14] sulfated peptides, [15] and heparin-like oligosaccharides [1c, 16] also compete with HS to block cell signaling and proliferation in vitro. Apart from polyanionic polymers such as sulfated polysaccharides, [7] poly(N-acrylamino acids), [8] sulfonic acid polymers, [9] hydroxylated and carboxylated polyaromatic compounds, [10] and oligoribonucleic acids, [11] small-molecule candidates derived from dipeptides, [12] glycoconjugates, [13] suramin and its analogues, [14] sulfated peptides, [15] and heparin-like oligosaccharides [1c, 16] also compete with HS to block cell signaling and proliferation in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…Many classes of structurally diverse HS mimetics have been shown to bind FGF- (1,2) and/or VEGF. Apart from polyanionic polymers such as sulfated polysaccharides, [7] poly(N-acrylamino acids), [8] sulfonic acid polymers, [9] hydroxylated and carboxylated polyaromatic compounds, [10] and oligoribonucleic acids, [11] small-molecule candidates derived from dipeptides, [12] glycoconjugates, [13] suramin and its analogues, [14] sulfated peptides, [15] and heparin-like oligosaccharides [1c, 16] also compete with HS to block cell signaling and proliferation in vitro. The above studies have provided some knowledge of the location, number, and pattern of sulfates required for binding, but have also pointed to the importance of hydrogen bonding and hydrophobic interactions.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template

Liu

Li²,

Cochran³

et al. 2012

ChemMedChem

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A disulfated methyl 6-azido-6-deoxy-α-D-mannopyranoside template was used as a core structure for binding to the angiogenic growth factors FGF-1, FGF-2, and VEGF. The core structure was diversified in a rapid, parallel manner by employing the Cu(I)-catalyzed Huisgen azide-alkyne cycloaddition ("click") reaction. The diversity was further extended by incorporating a Swern oxidation-Wittig reaction sequence on a click adduct of propargyl alcohol. Thus, the sulfated core was linked by various spacers to selected hydrophobic or polar motifs, which were designed to probe the protein surface surrounding the cationic heparan sulfate binding sites of the growth factors in order to improve affinity and selectivity. The affinities of the compounds for the growth factors were measured by surface plasmon resonance solution affinity assays. A lead compound was identified with micromolar binding affinity toward both FGF-1 and VEGF (K(d)=84 and 49 μM, respectively) and good selectivity over FGF-2 (29- and 51-fold, respectively).

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template

Liu

Li²,

Cochran³

et al. 2012

ChemMedChem

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“…Although the potency of these oligosaccharides appeared to be less pronounced than that of H/HS, both binding of FGF to FGF receptors and FGF-mediated mitogenic activity were significantly enhanced. Similarly, a diverse library of nonsulfated glucuronic acid (monosaccharide) derivatives ( 3 ) has been recently generated, several members of which competitively inhibited heparin binding to FGF-2 . Consequently, these results support the notion that tailored and precisely defined nonsulfated HS-related disaccharide modules or their homologues could serve as a significant tool for studying receptor protein binding in GAG-mediated events (Figure ).…”

Section: Introductionmentioning

confidence: 79%

Design and Synthesis of Dimeric Heparinoid Mimetics

et al. 2004

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Synthetic oligosaccharide constructs exhibiting tailored and well-defined heparan sulfate (HS) like sequences offer the potential to modulate dynamic HS-dependent biomolecular recognition processes. We report an efficient strategy for the generation of HS-like fragments [GlcA-beta-(1,4)-GlcNAc] and related dimerized (gemini) disaccharides (4a and 4b) via n-pentenyl glycoside formation. When a convergent synthetic approach was utilized, construction of target molecules was achieved through a combination of chemoselective protection/deprotection protocols, imidate and n-pentenyl glycosylations, and functional group manipulations followed by ozonolysis and reductive amination. For example, glycosylation of a 2-azido glycoside (25) with a trichloroacetimidate glucuronic acid donor (13), using a catalytic amount of TMSOTf, furnished heparin-like disaccharides (28a and 28b) that were equipped with an n-pentenyl tether at the anomeric end. In turn, heparinoid-like gemini disaccharides (4a and 4b) were produced by selective transformation of the olefinic unit in the n-pentenyl glycoside to the four-carbon aldehyde followed by reductive amination with ethylenediamine. The described synthetic approach provides access to structural variants of small heparinoid oligomers as versatile building blocks for generating novel HS mimetic pharmacotherapeutics, diagnostic reagents, and biomaterials.

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“…Hindsgaul and co-workers [98] have shown that evaluation of carbohybrid libraries composed of D-galactopyranose that carry a diverse range of small non-carbohydrate aglycon structures led to the identification of M inhibitors of a galactose binding plant lectin. Murphy et al [99] reported the identification of novel glucuronic acid derivatives that inhibited heparin binding to FGF-2 in enzyme linked immunosorbant assays (ELISAs). Murphy et al [99] reported the identification of novel glucuronic acid derivatives that inhibited heparin binding to FGF-2 in enzyme linked immunosorbant assays (ELISAs).…”

Section: Glycosides and Spaced Sugarsmentioning

confidence: 99%

Chemistry and Biology of Heparin Mimetics that Bind to Fibroblast Growth Factors

Hassan

2007

MRMC

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We aim from this review to stimulate further research in this area by providing a description of the different types of inhibitors containing heparin mimetic molecules that have recently been reported and data on their biological activity. Molecules that mimic heparin and bind to heparin-binding growth factors are important building blocks for synthetic biomaterials. Different types of synthetic mimics of the biological properties of heparin have been prepared inclu-ding high molecular weight compounds or small molecule mimics. Peptide-based mimics of heparin functionality are limited and because of their low degree of sulfation, they are natural targets as heparin mimics. Aromatic sulfonamide derivatives exhibit a range of bioactivities and a novel angiogenesis inhibitor (E 7820) is used as a TF model for screening assay. The anticoagulant activity of the known heparin pentasaccharide sequence prompted synthetic efforts aimed at the procurement of this structure as well as a host of related sequences. Chemical modification of the natural or synthetic heparin increased factor activation of AT III Xa affinity. A variety of non-peptide non-saccharides inhibitors as anti-angiogenesis therapies directed against the VEGFR kinase are a promising and well-validated therapeutic approach under active evaluation of their safety and efficacy in multiple clinical trials. These low molecular weight modulators could be useful tools for biologists and may have potential as drugs or as leads for drug development.

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Identification of novel inhibitors of fibroblast growth factor (FGF-2) binding to heparin and endothelial cell survival from a structurally diverse carbohybrid library

Cited by 23 publications

References 14 publications

Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template

Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template

Design and Synthesis of Dimeric Heparinoid Mimetics

Chemistry and Biology of Heparin Mimetics that Bind to Fibroblast Growth Factors

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