Synthesis and heparanase inhibitory activity of sulfated mannooligosaccharides related to the antiangiogenic agent PI-88.

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Fairweather JK, Hammond E, Johnstone KD, Ferro V

Synthesis and heparanase inhibitory activity of sulfated mannooligosaccharides related to the antiangiogenic agent PI-88.

Bioorg Med Chem. 2008 Jan 15;16(2):699-709. Epub 2007 Oct 18.

PubMed ID
17967543 [ View in PubMed
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Abstract

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.

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