Design and Synthesis of Neutralizable Fondaparinux

Abstract

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.

Synthesis of Anticoagulant Pentasaccharide Fondaparinux via 3,5-Dimethyl-4-(2′-phenylethynylphenyl)phenyl Glycosides

“…It was noteworthy that the pH of the reaction was maintained by slow addition of 1 M NaOH solution. The NMR data and high-resolution mass spectra (HRMS) of the synthetic 1 were identical to those reported in the literature for fondaparinux …”

“…By the early 1980s, a unique pentasaccharide domain of heparin was found to be clinically effective; 20 years later, fondaparinux ( 1 , Arixtra), a structurally homogeneous pentasaccharide, was clinically approved as an alternative of heparin to treat thrombotic events . Compared with heparin and low-molecular weight heparin, fondaparinux is industrially obtained by chemical synthesis, and exhibits a longer half-life and better antithrombotic efficacy and biosafety . Over the past few decades, many glycosylation methods and strategies have been applied to the synthesis of heparin fragments and relevant oligosaccharides .…”

“…Over the past few decades, many glycosylation methods and strategies have been applied to the synthesis of heparin fragments and relevant oligosaccharides . However, glycosylation methods which have been successfully applied to the synthesis of anticoagulant fondaparinux are rare …”

Chemoenzymatic Total Synthesis of Haemophilus ducreyi Lipooligosaccharide Core Octasaccharides Containing Natural and Unnatural Sialic Acids

“…The chemical synthesis of 1 remains challenging due to the requirement of the efficient preparation of multiple higher-carbon sugar building blocks such as l , d -Hep, d , d -Hep, and Kdo, as well as the stereoselective construction of glycosidic bonds. − It was assumed that protected hexasaccharide would be synthesized through a convergent and stereocontrolled [3 + 3] method from appropriately protected monosaccharide building blocks 7 – 12 . The ability to selectively remove orthogonal protecting groups 2-naphthylmethyl (Nap) , and levulinoyl (Lev) , as the corresponding acceptors makes it possible to glycosylate the C4 position of the l , d -Hep residue and the C6 position of the glucose (Glc) residue, respectively. Furthermore, anomeric methyl glycoside can be selectively converted to hemiacetals for the preparation of glycosyl donors for glycosylations.…”

“…Benzylation of the C6 hydroxyl of 17 with benzyl bromide (BnBr), NaH, and catalytic tetrabutylammonium iodide (TBAI) gave compound 8 . Cleavage of the Nap ether of 8 utilizing 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a mixture solution of dichloromethane (DCM) and phosphate buffer (PBS, pH 7.4) without impacting other protecting groups , provided glycosyl acceptor 18 , which was coupled with thioglycoside donor 7 using N -iodosuccinimide (NIS) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) to form β-linked disaccharide 19 ( J H1–H2 = 8.1 Hz) due to the neighboring-group participation effect of 2- O -Bz. The treatment of 19 with 80% acetic acid (AcOH) in water for the cleavage of isopropylidene acetals gave a 2,3-diol intermediate, followed by acylation with benzoyl chloride (BzCl) in pyridine to afford compound 20 .…”