Chemical Fucosylation of a Polysaccharide: A Semisynthetic Access to Fucosylated Chondroitin Sulfate

Abstract

Chemical O-glycosylation of polysaccharides is an almost unexplored reaction. This is mainly due to the difficulties in derivatizing such complex biomacromolecules in a quantitative manner and with a fine control of the obtained structural parameters. In this work, chondroitin raw material from a microbial source was chemo- and regioselectively protected to give two polysaccharide intermediates, that acted in turn as glycosyl acceptors in fucosylation reactions. Further manipulations on the fucosylated polysaccharides, including multiple de-O-benzylation and sulfation, furnished for the first time nonanimal sourced fucosylated chondroitin sulfates (fCSs)-polysaccharides obtained so far exclusively from sea cucumbers (Echinoidea, Holothuroidea) and showing several very interesting biological activities. A semisynthetic fCS was characterized from a structural point of view by means of 2D-NMR techniques, and preliminarily assayed in an anticoagulant test.

A Modular Approach to a Library of Semi‐Synthetic Fucosylated Chondroitin Sulfate Polysaccharides with Different Sulfation and Fucosylation Patterns

“…Indeed,atoo highly sulfated GAG such as per-Osulfated chondroitin can induce as trong allergic-type response, [10] as demonstrated by hundreds of serious adverse events, including 149 deaths, [11] whicho ccurred after the contamination of some heparin lots with per-O-sulfated chondroitin. [16] Ap reliminary anticoagulant assay revealed an activity profile similart ol ow-molecular-mass fCS polysaccharides obtained from natural sources, thus encouraging us to furtherw ork on this topic. [13] As low-molecular-mass fCS polysaccharides do not show these adversee ffects, many efforts have recently been devoted to the developmentofm ild and selective depolymerization methods aimed at shortening the fCSp olymer chain without cleaving the sulfate groups as well as the labile Fuc branches.…”

“…[20] The residual endotoxin content was evaluated by using the limulus amebocyte lysate (LAL) test andf ound to be lower than 0.1 EU mg À1 . After ap reliminary esterification of GlcA carboxylic acid and protection of GalNAc4 ,6-diol as benzylidene to convert CS-0 into polysaccharide 1, [16] five reactions werea pplied in two different sequences to access fCSs and fCsw ith Fuc branchesp laced exclusively on either the GlcA or GalNAc units. After ap reliminary esterification of GlcA carboxylic acid and protection of GalNAc4 ,6-diol as benzylidene to convert CS-0 into polysaccharide 1, [16] five reactions werea pplied in two different sequences to access fCSs and fCsw ith Fuc branchesp laced exclusively on either the GlcA or GalNAc units.…”

“…The polysaccharide acceptors for Fuc branching on GlcA or GalNAc were 1 and 8,r espectively.T he former was already known [16] and served also for the synthesis of the latter in two steps (Scheme 3). First, the 2,3-diol on the GlcA units was pro- Scheme2.Synthesis of Fuc donors 2, 3,and 4.…”

Synthesis and biological evaluation of acylated oligorhamnoside derivatives structurally related to mezzettiaside-6 with cytotoxic activity

“…1-2), 2.70-2.80 (m, 4H, 2 × COCH 2 ), 2.46 (dt, 1H, J = 16.1, 7.5 Hz, COCH 2 -1), 2.34 (dt, 1H, J = 16.0, 7.6 Hz, COCH 2 -2), 2.22, 2.14, 2.13 (each s, each 3H, each CH 3 CO), 1.63-1.66 (m, 2H, CH 2 ), 1.54-1.59 (m, 2H, CH 2 ), 1.26-1.34 (m, 14H, CH 2 ), 1.18 (d, 3H, J = 6.4 Hz, H-6′), 1.17 (d, 3H, J = 6.3 Hz, H-6″), 0.90 (t, 3H, J = 7.2 Hz, CH 3 ), 0.89 (t, 3H, J = 7.2 Hz, CH 3 ); 13 C NMR (CDCl 3 ): δ 206.1, 173.1, 171.9, 171.5, 170.2, 99.1, 97.1, 74.9, 74.3, 72.9, 72.2, 71.9, 68.1, 67.8, 66.8, 66.6, 37.8, 34.0, 31.8, 31.3, 29.8, 29.3 (two), 29.2, 28.2, 26.1, 24.5, 22.6, 22.3, 21.0, 20.9, 17.5, 17.2, 14.1, 13.9; HRMS(ESI-TOF): calcd for C 35 H 58 O 14 Na [M + Na] + 725.3724; found, 725.3732.p-Tolyl 2,4-di-O-acetyl-1-thio-α-L-rhamnopyranoside(4). To a solution of compound 17 (2.5 g, 9.4 mmol) in dry DMF (30 mL), triethylorthoacetate (2.4 mL, 14.0 mmol) was added, followed by a catalytic amount of CSA (434 mg, 1.9 mmol).…”

Synthesis of Fucosylated Chondroitin Sulfate Nonasaccharide as a Novel Anticoagulant Targeting Intrinsic Factor Xase Complex

“…[5] In vivo,t he nonasaccharide showed strong inhibition of venous thrombus in rats and had no obvious bleeding risk as compared with the clinical drug enoxaparin, thus attracting special interest as ap otential candidate drug. [8] Recently,o ur research group developed as ynthetic approach to FuCS trisaccharides and prepared aseries of glycoclusters. Thetotal synthesis of FuCS trisaccharide has been accomplished by Tamura et al over 16 linear steps in 0.95 %yield.…”