Synthesis and heparanase inhibitory activity of sulfated mannooligosaccharides related to the antiangiogenic agent PI-88.
A stepwise synthetic route to the mannooligosaccharides from the neutral fraction of Pichia holstii phosphomannan hydrolysate, including a tetrasaccharylamine component, was developed using only two or three readily available d-mannose building blocks. These compounds were sulfonated to give the corresponding sulfated oligosaccharides which are closely related to the constituents of the anticancer agent PI-88. The synthetic approach is well suited to the preparation of analogues as demonstrated by the synthesis of a series of (1-->3)-linked mannooligosaccharides. The inhibitory activity of the sulfated oligosaccharides against heparanase was determined using a Microcon ultrafiltration assay. The tetra- and pentasaccharides were potent competitive inhibitors of heparanase (K(i)=200-280nM) whilst the shorter di- and trisaccharides were partial competitive inhibitors and did not completely inhibit the enzyme even at very high concentrations.
Fairweather
Jon K
JK
Drug Design Group, Progen Pharmaceuticals Limited, PO Box 2403, Toowong, Qld 4066, Australia.
Hammond
Edward
E
Johnstone
Ken D
KD
Ferro
Vito
V
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D015394:Molecular Structure; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010843:Pichia / Q000737:chemistry*; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000099175:Heparanase
D020533:Angiogenesis Inhibitors; D005966:Glucuronidase; D009844:Oligosaccharides; D013463:Sulfuric Acid Esters; D000099175:Heparanase; C120158:phosphomannopentaose sulfate