Oligosaccharides aberrantly expressed on
tumor cells influence processes such as cell adhesion and modulation of the cell's microenvironment resulting in an increased
malignancy. Schmidt's imidate strategy offers an effective method to synthesize libraries of various
oligosaccharide mimetics. With the aim to perturb interactions of
tumor cells with
extracellular matrix proteins and host cells, molecules with 3,4-bis(hydroxymethyl)furan as core structure were synthesized and screened in
biological assays for their abilities to interfere in cell adhesion and other steps of the metastatic cascade, such as
tumor-induced angiogenesis.The most active compound, (4-{[(β-D-galactopyranosyl)oxy]methyl}
furan-3-yl)methyl
hydrogen sulfate (GSF), inhibited the activation of matrix-metalloproteinase-2 (MMP-2) as well as migration of the human
melanoma cells of the lines WM-115 and WM-266-4 in a two-dimensional migration assay. GSF inhibited completely the adhesion of WM-115 cells to the extracellular matrix (ECM)
proteins,
fibrinogen and
fibronectin.In an in vitro angiogenesis assay with human endothelial cells, GSF very effectively inhibited endothelial tubule formation and sprouting of blood vessels, as well as the adhesion of endothelial cells to ECM
proteins. GSF was not cytotoxic at biologically active concentrations; neither were 3,4-bis{[(β-D-galactopyranosyl)oxy]methyl}
furan (BGF) nor methyl β-D-
galactopyranoside nor 3,4-bis(hydroxymethyl)furan, which were used as controls, eliciting comparable
biological activity. In silico modeling experiments, in which binding of GSF to the extracellular domain of the
integrin α(v)β(3) was determined, revealed specific docking of GSF to the same binding site as the natural peptidic
ligands of this
integrin. The
sulfate in the molecule coordinated with one
manganese ion in the binding site.These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis(hydroxymethyl)furan and benzoylated
galactose imidate, is nontoxic and antagonizes cell physiological processes in vitro that are important for the dissemination and growth of
tumor cells in vivo.