Synthesis of AIDS Drug by Using of Sulfated Alkyl Oligosaccharides

以寡糖为原料，合成了具有体外抗艾滋病病毒活性的烷基寡糖硫酸酯。该方法的关键反应是长链烷基与寡糖还原端的键合，采用高效液相色谱和柱色谱相结合的方法，解决了中等分子量化合物分离纯化困难的问题，获得了高活性的目标化合物。考察了寡糖和烷基的结构和残基数目对反应的影响，（缩写为L）和具有4至7个葡萄糖残基的麦芽寡糖（M）、硫酸化烷基寡糖如硫酸化十二烷基昆布五糖苷本文合成了三种不同结构的半乳糖醛酸（简称SL 5-C12）、SL 5-C18、SL 9-C12、SL 9-C18、SM 4-C12、SM 5-C12、SM 7-C12、SM 7-C18等。此外，还用支链烷基、手性烷基、芳烷基和氟烷基取代了正烷基，并用MT-4细胞和HTLV-1病毒测定了这些化合物的抗HIV活性<HIB>。结果表明，十二烷基昆布五糖苷硫酸酯具有很高的抗HIV活性，其EC_0<50>为0.1 μ g/mL。该化合物经静脉注射给小鼠后，半衰期相当长，约为10 ~ 20 h。通过可得然胶的酶促降解和酸水解尝试了海带五糖的大规模生产，揭示了能够通过长时间色谱法进行化合物与寡糖混合物的分离。

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.