Ustyuzhanina NE et al. (2015), Synthesis of the oligosaccharides related to br...

ECB-ART-43822

Mar Drugs 2015 Feb 02;132:770-87. doi: 10.3390/md13020770.

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Synthesis of the oligosaccharides related to branching sites of fucosylated chondroitin sulfates from sea cucumbers.

Ustyuzhanina NE , Fomitskaya PA , Gerbst AG , Dmitrenok AS , Nifantiev NE .

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Natural anionic polysaccharides fucosylated chondroitin sulfates (FCS) from sea cucumbers attract great attention nowadays due to their ability to influence various biological processes, such as blood coagulation, thrombosis, angiogenesis, inflammation, bacterial and viral adhesion. To determine pharmacophore fragments in FCS we have started systematic synthesis of oligosaccharides with well-defined structure related to various fragments of these polysaccharides. In this communication, the synthesis of non-sulfated and selectively O-sulfated di- and trisaccharides structurally related to branching sites of FCS is described. The target compounds are built up of propyl β-d-glucuronic acid residue bearing at O-3 α-l-fucosyl or α-l-fucosyl-(1→3)-α-l-fucosyl substituents. O-Sulfation pattern in the fucose units of the synthetic targets was selected according to the known to date holothurian FCS structures. Stereospecific α-glycoside bond formation was achieved using 2-O-benzyl-3,4-di-O-chloroacetyl-α-l-fucosyl trichloroacetimidate as a donor. Stereochemical outcome of the glycosylation was explained by the remote participation of the chloroacetyl groups with the formation of the stabilized glycosyl cations, which could be attacked by the glycosyl acceptor only from the α-side. The experimental results were in good agreement with the SCF/MP2 calculated energies of such participation. The synthesized oligosaccharides are regarded as model compounds for the determination of a structure-activity relationship in FCS.

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Genes referenced: LOC100887844

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References [+] :

Borsig, Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. Effect on tumor metastasis and neutrophil recruitment. 2007, Pubmed, Echinobase

	Figure 1. Branched fragments of fucosylated chondroitin sulfates from sea cucumbers.
	Figure 2. The target compounds 1–8 related to branching sites of fucosylated chondroitin sulfates (FCS).
	Figure 3. Monosaccharide building blocks applied for the synthesis of FCS related oligosaccharides.
	Figure 4. Expected non-stabilized (I) and stabilized (II), (III) fucosyl cations in glycosylation reactions of fucosyl donor 12. 3D structures of cations were obtained by SCF/MP2 method.
	Scheme 1. Synthesis of the disaccharides 1–5. Reagents and conditions: (i) TMSOTf, CH2Cl2, −30 °C, 92%; (ii) (NH2)2CS, collidine, MeOH, 94%; (iii) Bu2SnO, BzCl (1.1 eq), 80%; (iv) (a) H2, Pd(OH)2/C; (b) LiOH, H2O, THF; (c) NaOH, H2O, 79%; (v) (a) AcCl, Py; (b) H2, Pd(OH)2/C; (c) SO3·Py, DMF; (d) Amberlite IR-120 (Na+), NaHCO3; (e) LiOH, H2O, THF; (f) NaOH, H2O, 64%; (vi) (a) SO3·Py, DMF; (b) Amberlite IR-120 (Na+), NaHCO3; (c) H2, Pd(OH)2/C; (d) LiOH, H2O, THF; (e) NaOH, H2O, 62%; (vii) (a) H2, Pd(OH)2/C; (b) SO3·Py, DMF; (c) Amberlite IR-120 (Na+); NaHCO3; (d) LiOH, H2O, THF; (e) NaOH, H2O, 52%.
	Scheme 2. Preparation of the difucoside donor 18. Reagents and conditions: (i) (a) TMSOTf, CH2Cl2, −30 °C; (b) (ClСH2CO)2O, Py, 78%; (ii) (a) PdCl2, MeOH; (b) CCl3CN, Cs2CO3, 84%.
	Scheme 3. Synthesis of the trisaccharides 6–8. Reagents and conditions: (i) TMSOTf, CH2Cl2, −30 °C, 90%; (ii) (NH2)2CS, collidine, MeOH, 92%; (iii) (a) H2, Pd(OH)2/C; (b) LiOH, H2O, THF; (c) NaOH, H2O, 82%; (iv) (a) AcCl, Py, (b) H2, Pd(OH)2/C; (c) SO3·Py, DMF; (d) Amberlite IR-120 (Na+), NaHCO3; (e) LiOH, H2O, THF; (f) NaOH, H2O, 54%; (v) (a) SO3·Py, DMF; (b) Amberlite IR-120 (Na+), NaHCO3; (c) H2, Pd(OH)2/C; (d) LiOH, H2O, THF; (e) NaOH, H2O, 62%.