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Mar Drugs
2016 Sep 21;149:. doi: 10.3390/md14090170.
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Depolymerization of Fucosylated Chondroitin Sulfate with a Modified Fenton-System and Anticoagulant Activity of the Resulting Fragments.
Li JH
,
Li S
,
Zhi ZJ
,
Yan LF
,
Ye XQ
,
Ding T
,
Yan L
,
Linhardt RJ
,
Chen SG
.
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Fucosylated chondroitin sulfate (fCS) from sea cucumber Isostichopus badionotus (fCS-Ib) with a chondroitin sulfate type E (CSE) backbone and 2,4-O-sulfo fucose branches has shown excellent anticoagulant activity although has also show severe adverse effects. Depolymerization represents an effective method to diminish this polysaccharide''s side effects. The present study reports a modified controlled Fenton system for degradation of fCS-Ib and the anticoagulant activity of the resulting fragments. Monosaccharides and nuclear magnetic resonance (NMR) analysis of the resulting fragments indicate that no significant chemical changes in the backbone of fCS-Ib and no loss of sulfate groups take place during depolymerization. A reduction in the molecular weight of fCS-Ib should result in a dramatic decrease in prolonging activated partial thromboplastin time and thrombin time. A decrease in the inhibition of thrombin (FIIa) by antithromin III (AT III) and heparin cofactor II (HCII), and the slight decrease of the inhibition of factor X activity, results in a significant increase of anti-factor Xa (FXa)/anti-FIIa activity ratio. The modified free-radical depolymerization method enables preparation of glycosaminoglycan (GAG) oligosaccharides suitable for investigation of clinical anticoagulant application.
Figure 1. Effect of different reaction conditions on the molecular weights (Mws) of depolymerized fCS from sea cucumber Isostichopus badionotus. (A) pH; (B) the concentration of H2O2; (C) the concentration of Cu2+; and (D) reaction temperature.
Figure 2. Polyacrylamide gel electrophoretograms of the fCS-Ib hydrolytic products. The products formed in the course of oxidative degradation with Fenton system were analyzed at different intervals with a 22% gel.
Figure 3. 1H nuclear magnetic resonance (NMR) spectra (800 MHz at room temperature) of the native and three depolymerized fCS-Ib samples. The assignment of the peak is explained in the figure and the references [18].
Figure 4. The 2D NMR spectra of DfCS-5 prepared by Fenton system (pH 6.0) at the concentration of 0.2 mol/L H2O2 and 0.2 mmol/L Cu2+ and at 55 °C: (A) Correlation spectroscopy (COSY) and (B) Total correlation spectroscopy (TOCSY). Signals designated with a reference to those produced by Fuc2,4S; and signals designated with G and u refer to N-acetyl-d-galactosamine (GalNAc) and glucuronic acid (GlcA), respectively.
Figure 5. Effect of fCS-Ib and its depolymerized products on inhibition of FIIa and FXa activity. (A) FXa/AT; (B) FIIa/AT; (C) FXa/HCII. AT (1 IU/mL) or HCII (0.5 mmol/L) were incubated with FIIa (20 IU/mL) or FXa (0.4 IU/mL) in the presence of fCS and its depolymerized products at various concentrations. After 120 s of incubation at 37 °C, the remaining FIIa or FXa was determined with a chromogenic substrate (A405 nm/min). Results were shown as means ± SD (n = 3/group).
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