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.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Glycosides/chemical synthesis , Heparitin Sulfate/chemistry , Oligosaccharides/chemical synthesis , Sulfuric Acid Esters/chemical synthesis , 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 AssaysABSTRACT
The heparan sulfate (HS) mimetic PI-88 is a promising inhibitor of tumor growth and metastasis expected to commence phase III clinical evaluation in 2007 as an adjuvant therapy for postresection hepatocellular carcinoma. Its anticancer properties are attributed to inhibition of angiogenesis via antagonism of the interactions of angiogenic growth factors and their receptors with HS. It is also a potent inhibitor of heparanase, an enzyme that plays a key role in both metastasis and angiogenesis. A series of PI-88 analogs have been prepared with enhanced chemical and biological properties. The new compounds consist of single, defined oligosaccharides with specific modifications designed to improve their pharmacokinetic properties. These analogs all inhibit heparanase and bind to the angiogenic fibroblast growth factor 1 (FGF-1), FGF-2, and vascular endothelial growth factor with similar affinity to PI-88. However, compared with PI-88, some of the newly designed compounds are more potent inhibitors of growth factor-induced endothelial cell proliferation and of endothelial tube formation on Matrigel. Representative compounds were also tested for antiangiogenic activity in vivo and were found to reduce significantly blood vessel formation. Moreover, the pharmacokinetic profile of several analogs was also improved, as evidenced primarily by lower clearance in comparison with PI-88. The current data support the development of HS mimetics as potent antiangiogenic anticancer agents.
