Synthesis of AIDS Drug by Using of Sulfated Alkyl Oligosaccharides

以低聚糖为原料，合成了体外抗艾滋病病毒(HIV)活性较高的烷基低聚糖。磺化烷基低聚糖的关键反应是长烷基与低聚糖还原端的结合，高相对分子质量化合物的分离和纯化困难主要通过高效柱层析和精制的脱盐过程来解决，从而得到高活性的目标化合物。考察了低聚糖和烷基的结构和残基数目对低聚糖和烷基结构的影响，合成了以含5~9个葡萄糖残基的海带低聚糖(简称L)和含4~7个葡萄糖残基的麦芽低聚糖(M)为原料，磺化十二烷基海带-五糖苷(简称SL5-C12)、SL5-C18、SL9-C12、SL9-C18、SM4-C12、SM5-C12、SM7-C12、SM7-C18等烷基低聚糖。此外，还研究了取代正烷的支链烷基、手性烷基、芳烷基和氟烷基。通过MT-4细胞和HTLV-HIB&GT；病毒检测了这些化合物的抗HIV活性。结果表明，十二烷基层析五苷具有较高的抗HIV活性，EC_(50)和GT_(50)为0.1mug/mL，是较理想的化合物。该化合物静脉注射给小鼠，半衰期较长，约为10~20小时。通过对凝胶聚糖的酶降解和酸性水解法进行了规模化生产，发现可以用长时间层析的方法从低聚糖混合物中分离出该化合物。

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.