دانلود رایگان مقاله ویژگی های ساختاری HPSE - مهار هپارین غیر ضد انعقاد مشتق Roneparstat

Abstract

Owing to their anti-tumor and anti-inflammatory properties, non-anticoagulant glycol-split (gs) heparins, obtained by periodate oxidation/borohydride reduction, are of growing interest. The present study was focused on the structural characterization of N-acetylated gs-heparin Roneparstat, a promising anti-cancer heparanase-inhibiting drug currently being investigated in clinical trials. The major and minor structural features of structurally complex Roneparstat have been characterized for the first time using conductimetric titration, size-exclusion chromatography with triple detector array, NMR and LC/MS. It has been shown that gs-uronic acids are mainly interspersed by unmodified disaccharide building blocks, but can also be present within sequences with consequent gs-residues. Peculiar gs-sequences, such as those derived from antithrombin binding regions and those containing I2S-ANS3S6S, as well as a variety of unnatural terminal groups, markers of preparation processes, have also been identified in Roneparstat. Structural features of Roneparstat that may play an important role in interactions with proteins have been summarized.

5. Conclusions

The development of efficient and complementary analytical techniques has become increasingly importantto structurally characterize complex GAG-based biologically active products, to assist in their derivatization under controlled conditions as well as to help study their interaction with proteins and other biomacromolecules, for the purpose of rationalizing the search of new potential drugs. In the present study the structural features of the biologically active Roneparstat, being currently studied in clinical trials as nonanticoagulant heparanase-inhibitor, have been studied for the first time.A combination of conductimetric titration, SEC-TDA, NMR and LC–MS analysis of the enzymatically digested samples, provides complementary structural information concerning major and minor internal sequences as well as terminal residues of SST0001 chains. The internal sequences are represented by a large variety of structures that may play an important role in interactions with proteins. The SST0001 internal domains comprise mainly repeating I2S-ANAc6S disaccharide building blocks interspersed by gs-uronic acids, predominantly one or two subsequent gs-residues.