Synthesis of a Heparinoid Pentasaccharide Containing L-Guluronic Acid Instead of L-Iduronic Acid with Preserved Anticoagulant Activity

Herczeg, Mihály and Demeter, Fruzsina and Lisztes, Erika and Racskó, Márk and Tóth, Balázs István and Timári, István and Bereczky, Zsuzsanna and E Kövér, Katalin and Borbás, Anikó (2022) Synthesis of a Heparinoid Pentasaccharide Containing L-Guluronic Acid Instead of L-Iduronic Acid with Preserved Anticoagulant Activity. JOURNAL OF ORGANIC CHEMISTRY, 87 (23). pp. 15830-15836. ISSN 0022-3263 (print); 1520-6904 (online)

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Abstract

L-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that L-iduronic acid can be replaced by an easier-to-produce L-sugar while maintaining its essential biological activity. From the inexpensive D-mannose, through a highly functionalized phenylthio mannoside, the L-gulose donor was prepared by C-5 epimerization in 10 steps with excellent yield. This unit was incorporated into the pentasaccharide by alpha-selective glycosylation and oxidized to L-guluronic acid. The complete synthesis required only 36 steps, with 21 steps for the longest linear route. The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of L-iduronic acid.

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