Abstract
A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1α), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Chemokine CXCL12 / antagonists & inhibitors
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Chemokine CXCL12 / metabolism
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Drug Design
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Female
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Fibroblast Growth Factor 2 / antagonists & inhibitors
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Fibroblast Growth Factor 2 / metabolism
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Heparin, Low-Molecular-Weight* / chemistry
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Heparin, Low-Molecular-Weight* / metabolism
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Heparin, Low-Molecular-Weight* / pharmacology
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High-Throughput Screening Assays
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Hydrolysis
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / pathology
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Neoplasm Transplantation
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Neovascularization, Pathologic / drug therapy*
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Neovascularization, Pathologic / prevention & control
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P-Selectin / antagonists & inhibitors
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P-Selectin / metabolism
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Protein Binding
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Small Molecule Libraries* / chemistry
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Small Molecule Libraries* / metabolism
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Small Molecule Libraries* / pharmacology
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Structure-Activity Relationship
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Sulfates / metabolism
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Surface Plasmon Resonance
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Chemokine CXCL12
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Heparin, Low-Molecular-Weight
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Membrane Glycoproteins
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P-Selectin
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P-selectin ligand protein
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Small Molecule Libraries
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Sulfates
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Fibroblast Growth Factor 2