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Structure-activity Relationship Study of Homogalacturonans Sulfated Derivatives with Anti-complementary Activity

王辉俊  Songshan Shi  Bin Bao  Chao Zhu  Hui Lian  Hongwei Fang  王顺春  
【摘要】:正Heparin,a highly sulfated copolymer composed of uronic acid and glucosamine,is recognized as one of the best characterized molecule that shows profound anti-complement activity.However,at the concentration sufficient to inhibit the complement system,heparin will demonstrate undesirable anti-coagulant side effect which limit its application in the treatment of anti-complementary diseases.The relationship between anti-complement activity and structure indicated that the uronic acid and sulfate groups of heparin were the necessary for the anti-complement activity. To find the agents with non-toxic strategies for the therapeutic inhibition of complement, we prepared heparin analogues(polysaccharides with uronic acids and sulfate groups), and further studied the structure activity relationship.It was reported that uronic acid exist in Capparis spinosa L.(CS),green tea(GT),and pre-infused green tea(PGT). However,the primary structures of the polysaccharides were unclear.After extraction, isolation,and purification,seven homogenous water-soluble polysaccharides were obtained from CS,GT,and PGT,with the molecular weight range from 0.88×104 Da to 6.7×10~4 Da.CSPS-2B-2 was obtained from CS,TPS4-2B,TPS4-2C from GT,TPSR4-2B, TPSR4-2C,FTPSR4-2B and FTPSR4-2C from PGT.A combination of composition, methylation and configuration analysis,as well as NMR spectroscopy,indicated that all of them were poly-(1-4)-α-D-Homogalacturonans(HG pectin) in which different percentage of uronic acid existed as methyl ester.21 kinds of sulfated derivatives (heparin Analogues) from these seven HG pectin,commercial HG pectin and Galacturonic acid were prepared after sulfation at different conditions. Bioassay on the complement and coagulation system of the heparin analogues demonstrated that:(1) Sulfate groups in sulfated derivatives of the HG pectin played a crucial role in the anti-complement and anti-coagulant activity;(2) The anti-complement activity of sulfated derivatives of HG pectin(DS from 0.48 to 1.69) weren't shown to depend on the sulfate content of the molecule;(3) Sulfated HG pectins exhibited strong anti-complement activity and low anti-coagulant activity with dose of 5.2μg/ml;(4) Anticomplement activity was stable when MW more than 0.7×10~4 Da,and MW had no influence on coagulation system activity;(5) Meanwhile,methyl ester had no influence on either anti-complement or anti-coagulant activity,(6) Sulfated derivatives of the HG pectins might interact with C1q,C1r,C1s,C2,C5 and C9,but not with C3 and C4.All of these results might provide some clue to discover heparin analogues as a promising candidate of an anti-complement agent.

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