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

Abstract

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).

Fluorous-tag assisted synthesis of a glycosaminoglycan mimetic tetrasaccharide as a high-affinity FGF-2 and midkine ligand

“…In addition, we studied the interaction between tetrasaccharide 1 and a different GAG-binding protein, FGF-2 (basic fibroblast growth factor), with a key role in angiogenesis and tumor cell growth. 22,24,54 Compounds that selectively recognize one GAG-binding protein are highly demanded. The analysis of the FP competition curves afforded an IC50 value of 2.4 ± 1.3 µM (see Supporting Information, Figure S3) that was again lower than the IC50 displayed by a CS-E persustituted tetrasaccharide derivative without the fluorous tag (42 µM).…”

“…Sulfated non-GAG oligosaccharides, such as mannose derivatives PI-88 and PG545, have also been reported as GAG mimetics with potent anticancer activity and high binding affinities to angiogenic growth factors. [22][23][24] Additionally, non-sugar, sulfated compounds bearing an aromatic scaffold are also potent modulators of GAG-protein binding. [25][26][27] The interaction of these highly hydrophobic analogues usually involves an important non-ionic contribution to binding energy.…”

Heparin Mimetics: Their Therapeutic Potential

“…Ferro and co-workers also synthesized an 18-membered library of small molecule HS mimetics via click chemistry. These mimetics were targeted against the angiogenic growth factors FGF-1, FGF-2 and VEGF [ 83 ]. The library of mimetics was designed with the specific aims of firstly, identifying the critical sulfate groups for binding on the monosaccharide ring, with the view to decreasing the overall sulfation without loss of activity, and secondly, to enable the exploration of possible non-ionic binding surfaces around the primary binding site on the proteins; the primary binding site being comprised of clusters of basic, positively charged amino acids.…”

“…The binding studies indicated that affinity and structural specificity of the mimetic was increased by the incorporation of non-anionic motifs. A lead compound was identified from the library with micromolar binding affinity towards FGF-1 and VEGF and good selectivity over FGF-2 [ 83 ]. This work illustrates the power of combining an anionic sugar structure with an aromatic spacer, of an appropriate length and rigidity, to position a polar group at a site on the protein removed from the binding hot-spot that recognizes the sulfate groups, for enhancing the specificity of the heparin mimetic.…”

Synthesis and evaluation of β-hydroxytriazoles and related compounds as antitubercular agents

“…Styryl triazole derivatives are scaffolds possessing various biological properties. For example, they were evaluated as potential ligands for angiogenic growth factors FGF-1, FGF-2 and VEGF [18] but also as candidates for β-amyloid (Aβ) plaque imaging [19]. The synthesis of styryl derivatives 4a-e was performed in two steps from the corresponding alcohol as shown in Table 3.…”