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活性高的硫酸烷基低聚糖。得到巯基低聚糖的关键反应是长烷基与低聚糖的还原端结合。中分子量化合物固有的分离纯化困难主要通过高效柱色谱法和精心设计的脱盐工艺来解决。结果，得到了具有高活性的目标化合物。考察了低聚糖和烷基基团的结构和残基数的影响。由此，从具有5 ~ 9个葡萄糖残基的层状寡糖（简称L）和具有4 ~ 7个葡萄糖残基的麦芽寡糖（简称M）开始，合成了磺化十二烷基层状五皂苷（简称SL5-C12）、SL5-C18、SL9-C12、SL9-C18、SM4-C12、SM5-C12、SM7-C12、SM7-C18等烷基寡糖。此外，支链烷基、手性烷基、芳烷基和氟烷基被用来代替正烷基。用MT-4细胞和HTLV-_<HIB>病毒检测了这些化合物的抗hiv活性。结果表明，磺化十二烷基层状戊酸皂苷具有较高的抗hiv活性，EC_<50>为0.1mug/mL。该化合物在小鼠体内静脉注射时，显示出相当长的半衰期，约为10至20小时。通过酶解和酸性水解法对层压戊糖进行了大规模生产，结果表明，该化合物可以通过长时间色谱法从低聚糖混合物中分离出来。

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.