Fondaparinux, a clinically approved anticoagulant pentasaccharide for the treatment of thrombotic diseases, displays better efficacy and biosafety than other heparin-based anticoagulant drugs. However, there is no suitable antidote available for fondaparinux to efficiently manage its potential bleeding risks, thereby precluding its widespread use. Herein, we describe a convergent and stereocontrolled approach to efficiently synthesize an aminopentyl-functionalized pentasaccharide, which is further used to prepare fondaparinux-based biotin conjugates and clusters. Biological activity evaluation demonstrates that the anticoagulant activity of the fondaparinux-based biotin conjugate and trimer is, respectively, neutralized by avidin and protamine as effective antidotes. This work suggests that our synthetic biotin conjugate and trimer have potential for the development of neutralizable and safe anticoagulant drugs.
The first total synthesis of Haemophilus ducreyi lipooligosaccharide core octasaccharides containing natural and
unnatural sialic acids has been achieved by an efficient chemoenzymatic
approach. A highly convergent [3 + 3] coupling strategy was developed
to chemically assemble a unique hexasaccharide bearing multiple rare
higher-carbon sugars d-glycero-d-manno-heptose (d,d-Hep), l-glycero-d-manno-heptose
(l,d-Hep), and 3-deoxy-α-d-manno-oct-2-ulosonic
acid (Kdo). Key features include sequential one-pot glycosylations
for oligosaccharide assembly and the construction of the challenging
α-(1 → 5)-linked Hep–Kdo glycosidic bond by gold-catalyzed
glycosylation with a glycosyl ortho-alkynylbenzoate
donor. Furthermore, the sequential enzyme-catalyzed regio- and stereoselective
introduction of a galactose residue using β-1,4-galactosyltransferase
and different sialic acids using a one-pot multienzyme sialylation
system was efficiently accomplished to provide the target octasaccharides.
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