Short synthesis of idraparinux by applying a 2-O-methyl-4,6-O-arylmethylene thioidoside as a 1,2-trans α-selective glycosyl donor

The fully O-sulfated, O-methylated, heparin-related anticoagulant pentasaccharide idraparinux was prepared by a new synthetic pathway in 38 steps using D-glucose and methyl α-D-glucopyranoside as starting materials, with 23 steps for the longest linear route. The L-idose-containing GH fragment was obtained by a short and straightforward synthesis whereby a 4,6-cyclic-acetal-protected L-idosyl thioglycoside bearing a C2-nonparticipating group was used as the α-selective glycosyl donor. The novel L-idose donor was prepared with high chemo- and stereoselectivity by hydroboration–oxidation-based C5 epimerization starting from an orthogonally protected α-thioglucoside. The assembly of the pentasaccharide backbone was achieved by an F+GH and DE+FGH coupling sequence with full stereoselectivity in each glycosylation step

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

One critical part of the synthesis of heparinoid anticoagulants is the creation of the L-iduronic acid building block featured with unique conformational plasticity which is crucial for the anticoagulant activity. Herein, we studied whether a much more easily synthesizable sugar, the 6-deoxy-L-talose, built in a heparinoid oligosaccharide, could show a similar conformational plasticity, thereby can be a potential substituent of the L-idose. Three pentasaccharides related to the synthetic anticoagulant pentasaccharide idraparinux were prepared, in which the L-iduronate was replaced by a 6-deoxy- L-talopyranoside unit. The talo-configured building block was formed by C4 epimerisation of the commercially available L-rhamnose with high efficacy at both the monosaccharide and the disaccharide level. The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable 1C4 chair conformation of their 6-deoxy-L-talopyranoside residues

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

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

Rhamnose Binding Protein as an Anti-Bacterial Agent-Targeting Biofilm of Pseudomonas aeruginosa

L

Védett, 6-dezoxi-L-talopiranozid tartalmú idraparinux analóg pentaszacharid szintézise

A dolgozat egy védett idraparinux analóg pentaszacharid előállítását tartalmazza, melyen az iduronsav egység 6-dezoxi-L-talopiranoziddal van helyettesítve. Ezen belül az F-és G monoszacharid egység, a GH diszacharid, illetve az FGH triszacharid építőelem szintézisét mutatja be.MSc/MAvegyészg