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Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Feb 25; Vol. 53 (4), pp. 1686-99. - Publication Year :
- 2010
-
Abstract
- A series of polysulfated penta- and tetrasaccharide glycosides containing alpha(1-->3)/alpha(1-->2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.
- Subjects :
- Angiogenesis Inhibitors pharmacokinetics
Angiogenesis Inhibitors pharmacology
Animals
Blood Coagulation drug effects
Drug Resistance, Neoplasm
Fibroblast Growth Factor 1 metabolism
Fibroblast Growth Factor 2 metabolism
Glucuronidase antagonists & inhibitors
Glycosides pharmacokinetics
Glycosides pharmacology
Humans
In Vitro Techniques
Male
Melanoma, Experimental blood supply
Melanoma, Experimental drug therapy
Melanoma, Experimental pathology
Mice
Mice, Inbred C57BL
Molecular Mimicry
Neovascularization, Pathologic drug therapy
Neovascularization, Physiologic drug effects
Oligosaccharides pharmacokinetics
Oligosaccharides pharmacology
Protein Binding
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Sulfuric Acid Esters pharmacokinetics
Sulfuric Acid Esters pharmacology
Vascular Endothelial Growth Factor A metabolism
Xenograft Model Antitumor Assays
Angiogenesis Inhibitors chemical synthesis
Glycosides chemical synthesis
Heparitin Sulfate chemistry
Oligosaccharides chemical synthesis
Sulfuric Acid Esters chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20128596
- Full Text :
- https://doi.org/10.1021/jm901449m