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Biomacromolecules
2021 Dec 13;2212:5151-5161. doi: 10.1021/acs.biomac.1c01112.
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Semisynthetic Isomers of Fucosylated Chondroitin Sulfate Polysaccharides with Fucosyl Branches at a Non-Natural Site.
Vessella G
,
Marchetti R
,
Del Prete A
,
Traboni S
,
Iadonisi A
,
Schiraldi C
,
Silipo A
,
Bedini E
.
Abstract
The several interesting activities detected for fucosylated chondroitin sulfate (fCS) have fueled in the last years several efforts toward the obtainment of fCS oligosaccharides and low molecular weight (LMW) polysaccharides with a well-defined structure, in order to avoid the problems associated with the potential employment of native, sea cucumber sourced fCSs as a drug. Total synthesis and controlled depolymerization of the natural fCS polysaccharides are the main approaches to this aim; nonetheless, they present some limitations. These could be circumvented by semisynthesis, a strategy relying upon the regioselective fucosylation and sulfation of a microbial sourced polysaccharide sharing the same chondroitin backbone of fCS but devoid of any fucose (Fuc) and sulfate decoration on it. This approach is highly versatile, as it could open access also to fCS isomers carrying Fuc and sulfate groups at non-natural sites. Here we prepare for the first time some structurally homogeneous fCS isomers through a multistep procedure with a glycosylation reaction between a LMW polysaccharide acceptor and three different Fuc donors as key step. The obtained products were subjected to a detailed structural characterization by 2D-NMR. The conformational behavior was also investigated by NMR and molecular dynamics simulation methods and compared with data reported for natural fCS.
Chart 1. Structure
of Natural fCS Polysaccharides and Chemically Obtained
Oligosaccharides and Low Mw Polysaccharides
Scheme 1. General Strategy to Access Semisynthetic Isomers of fCS Polysaccharides
from Microbial-Sourced Unsulfated ChondroitinPG = protecting group; TPG
= temporary protecting group; LG = leaving group.
Scheme 2. Semisynthesis of a Polysaccharide Acceptor with a Single Free Hydroxyl
at the GalNAc C-4 Position
Figure 1. 1H NMR spectra
(600 MHz, DMSO-d6, 298 K) of 8-b after one (up) or two (down)
fucosylation steps. Polysaccharide signal assignments are enclosed
in rectangles.
Scheme 3. Semisynthesis of fCS Polysaccharides 10-a–cPostulated structures are depicted
(for structural characterization, see text and Table 2).
Figure 2. (a) 1H and 1H,13C-DEPT-HSQC and
(b) COSY (black), TOCSY (blue), and NOESY (red) NMR spectra (600 MHz,
D2O, 298 K, zoom) of 10-c. Only some of the
assignments are indicated (for full assignments, see the Supporting Information).
Figure 3. (a) Representative structures of the most populated
clusters of
fCS 10-c extracted from the MD simulation (each structure
is differently colored). (b, c) Structure and molecular surface of
fCS 10-c structure of a representative conformer of the
most populated cluster from the MD simulation (fCS backbone is represented
in white and sulfate groups are represented in orange). (d) Key distances
between GlcNAc H-6 and Fuc H-5 (diagnostic of the orientation of the
Fuc ring with respect to the GalNAc-GlcA skeleton).
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