Synthesis of Polymeric AIDS Dryg with Lasting Activity

具有持久活性的高分子助剂的合成

• 批准号: 01850199
• 负责人: URYU Toshiyuki
• 金额: $ 7.55万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-01850199/
• 关键词: AIDS-virus drug; Curdlan sulfate; Lentinan sulfate; AIDS drug; L-Glucose-branched ribofuranan; Sulfated polysaccharide; Anti-HIV activity; Low anticoagulant activity; カ-ドラン硫酸; リボフラナン硫酸(RS); マンノピラナン硫酸(MS); 抗凝血活性; 硫酸化アルキルオリゴ糖; 硫酸化L糖分枝多糖; 生分解性

Such synthetic polysaccharides as ribofuranan, xylofuranan, and dextran sulfates showed not only high anti-AIDS virus (anti-HIV) activity, but also high anticoagulant activity which is assumed to be side effects. In this study, sulfated polysaccharides with high anti-HIV activity but low anticoagulant activity were for the first time synthesized. A 1, 3-beta-linked antitumor polysaccharide lentinan was sulfated with piperidine N-sulfonic acid to afford lentinan sulfate. Lentinan sulfate had high anti-HIV activity inhibiting completely AIDS virus infection to T lymphocytes in a concentration as low as 3.3 mug/ml in vitro. Moreover, it showed low anticoagulant activity of about 20 unit/mg. Next, a bacterial polysaccharide curdlan having the same backbone structure as lentinan was sulfated by the same method to give curdlan sulfate. Curdlan sulfate had a high anti-HIV activity which inhibits the virus infection in a a 3.3 mug/ml concentration, and showed low anticoagulant activity of 15 unit/mg. The curdlan sulfate introduced into animal blood was transported into such tissues as liver, kidney, lymph node, and bone marrow, disappearing from the blood in 60-180 minutes after injection. To keep the concentration of curdlan sulfate in blood in a high level for longer time, such nonnatural sugars as L-glucose and L-mannose were reacted with curdlan and syntheric ribofuranan to form L-glycosyl branchings. For L-glyscosyl-branched polysaccharide sulfates, in vivo retention time of the anticoagulant activity in blood was a few hours. It was revealed that the absorbed curdlan sulfate exisis in the tissue for a few ten days without being subjected to main chain degradation. Syntheric 1, 6-alpha-D-mannan sulfate had high anti-HIV activity and medium anticoagulant activity.

合成的核糖呋喃、木氯呋喃、葡聚糖硫酸盐等多糖不仅具有较高的抗艾滋病病毒活性，而且具有较高的抗凝血活性，这被认为是副作用。本研究首次合成了具有高抗hiv活性但低抗凝血活性的硫酸酸化多糖。以1,3 - β -连接的香菇多糖为研究对象，用哌啶n -磺酸对香菇多糖进行硫酸酸化，得到硫酸香菇多糖。硫酸香菇多糖具有较高的抗hiv活性，体外浓度低至3.3马克杯/毫升，可完全抑制艾滋病病毒对T淋巴细胞的感染。其抗凝血活性较低，约为20单位/mg。然后，采用相同的方法对具有与香菇多糖相同骨架结构的细菌多糖凝乳酶进行硫酸酸化，得到硫酸凝乳酶。硫酸铁多糖具有较高的抗hiv活性，浓度为3.3马克杯/毫升时可抑制病毒感染，抗凝血活性较低，为15单位/毫克。引入动物血液中的硫酸凝乳素被输送到肝脏、肾脏、淋巴结、骨髓等组织，注射后60-180分钟从血液中消失。为了使血液中硫酸凝乳素的浓度长时间保持在较高水平，将l -葡萄糖、l -甘露糖等非天然糖与凝乳素和合成的核糖呋喃反应形成l -糖基分支。l-糖基支链硫酸多糖在血液中抗凝血活性的体内保留时间为几小时。结果表明，吸收的硫酸凝乳素在组织中存在数天而不受主链降解。合成的1,6 - α - d -甘露聚糖硫酸酯具有较高的抗hiv活性和中等的抗凝血活性。

项目成果

Y.Kaneko et al.: "Complete Inhibition of HIV-1 Infectivity With Curdlan Sulfate in Vitro" Biochem.Pharm.39. 793-797 (1990)

Y.Kaneko 等人：“硫酸凝胶多糖在体外完全抑制 HIV-1 感染”Biochem.Pharm.39。

K.Hatanaka et al.: "Synthesis and Sulfation of Branched Dextrans" Polym.J.22. 435-441 (1990)

K.Hatanaka 等人：“支链葡聚糖的合成和硫酸化”Polym.J.22。

T.Uryu et al.: "Sulfated Alkyl Oligosaccharides with Porent Inhibitory Effects on Human Immunodeficiency Virus Infection" Biochem.Pharm.

T.Uryu 等人：“硫酸烷基寡糖对人类免疫缺陷病毒感染具有有效的抑制作用”Biochem.Pharm。

瓜生 敏之,吉田 孝: "「バイオ新素作」本宮 達也,松永 是編著" 日刊工業新聞社, 15 (1990)

Toshiyuki Uryu、Takashi Yoshida：“New Bio Draft”，由 Tatsuya Motomiya 和 Kore Matsunaga 编辑，日刊工业新闻，15（1990）

T.Yoshida et al.: "Synthesis of Branched Ribofuranans and Their Sulfates with Potent Anti-AIDS Virus Activity by Selective Ring-Opening Copolymerization of 1,4-Anhydro-α-D-ribopynose Derivatives" Macromolecules.

T. Yoshida 等人：“通过 1,4-脱水-α-D-核糖衍生物的选择性开环共聚，合成具有有效抗艾滋病病毒活性的支链呋喃核糖及其硫酸盐”大分子。