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Synthesis of AIDS Drug by Using of Sulfated Alkyl Oligosaccharides

硫酸烷基低聚糖合成艾滋病药物

基本信息

批准号：
06555283
负责人：
URYU Toshiyuki
金额：
$ 8.77万
依托单位：
UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Starting from oligosaccharides, sulfated alkyl oligosaccharides with high anti-AIDS virus (HIV) activity in vitro were synthesized. The key reaction affording the sulfated alkyl oligosaccharide was the binding of a long alkyl group to reducing end of an oligosaccharide.Difficulties in separation and purification which were inherent in the medium molecular weight compounds were mostly solved by use of high performance and column chromatographies in addition to an elaborated desalting process.As a result, the target compound with a high activity was obtained. Effects of the structure and residue number of both oligosaccharides and alkyl groups were examined.Thereby, starting both from laminari oligosaccharides (abbreviated as L) having 5 to 9 glucose residues and from malto oligosaccharides (M) having 4 to 7 glucose residues, sulfated alkyl oligosaccharides such as sulfated dodecyl laminari-pentaosides (abbreviated as SL5-C12), SL5-C18, SL9-C12, SL9-C18, SM4-C12, SM5-C12, SM7-C12, SM7-C18 and so on, were synthesized. Furthermore, branched alkyls, chiral alkyls, aralkyls, and fluoroalkyls were examined in place of the n-alkyl.For these various compounds, the anti-HIV activity was measured by means of MT-4 cells and HTLV-_<HIB> viruses. It was concluded that sulfated dodecyl laminaripentaoside which had a very high anti-HIV activity represented by EC_<50> of 0.1mug/mL was an optimum compound. This compound exhibited considerably long harf-life time of about 10 to 20 h, when it was intravenously injected to mice. A large scale production of laminaripentaose was tried by both enzymic degradation and acidic hydrolysis of curdlan, revealing that separation of the compound from the oligosaccharides mixture is able to be performed by long-time chromatography.

以低聚糖为原料，合成了体外具有高抗艾滋病病毒（HIV）活性的硫酸化烷基低聚糖。获得硫酸化烷基寡糖的关键反应是长烷基与寡糖还原端的结合。通过使用高效柱色谱以及精心设计的脱盐过程，大部分解决了中等分子量化合物固有的分离和纯化困难。最终获得了具有高活性的目标化合物。研究了低聚糖和烷基的结构和残基数的影响。由此，以具有5至9个葡萄糖残基的海带低聚糖(缩写为L)和具有4至7个葡萄糖残基的麦芽低聚糖(M)为起始，硫酸化烷基低聚糖例如硫酸化十二烷基昆布五糖苷合成了SL5-C12（简称SL5-C12）、SL5-C18、SL9-C12、SL9-C18、SM4-C12、SM5-C12、SM7-C12、SM7-C18等。此外，还检查了支链烷基、手性烷基、芳烷基和氟烷基来代替正烷基。对于这些不同的化合物，通过MT-4细胞和HTLV-_<HIB>病毒测量了抗HIV活性。结果表明，硫酸化十二烷基昆布五糖苷具有很高的抗HIV活性，其EC_<50>为0.1mug/mL，是最佳化合物。当该化合物静脉注射给小鼠时，其半衰期相当长，约为 10 至 20 小时。通过凝胶多糖的酶降解和酸水解尝试大规模生产昆布五糖，表明可以通过长时间色谱法将该化合物从寡糖混合物中分离出来。