Nishimura S I, Kai H, Shinada K, Yoshida T, Tokura S, Kurita K, Nakashima H, Yamamoto N, Uryu T
Graduate School of Science, Hokkaido University, Sapporo, Japan.
Carbohydr Res. 1998 Jan;306(3):427-33. doi: 10.1016/s0008-6215(97)10081-7.
A novel and convenient method for the regioselective syntheses of sulfated analogs of chitin and chitosan is described in relation to studies on structure-biological activity. Fully protected, soluble derivatives of chitosan were found to be useful intermediates for the syntheses of a novel class of sulfated polysaccharides, 2-acetamido-2-deoxy-3-O-sulfo-(1-->4)-beta-D-glucopyranan (3-sulfate, 3S, 4) and (1-->4)-2-deoxy-2-sulfoamido-3-O-sulfo-(1-->4)-beta-D-glucopyranan (2,3-disulfate, 23-S, 3). These compounds were tested for their activities in (i) inhibiting HIV-1 replication in vitro and (ii) inhibiting blood coagulation. The results reveal that the selective sulfation at O-2 and/or O-3 affords potent antiretroviral agents showing a much higher inhibitory effect on the infection of AIDS virus in vitro than that by the known 6-O-sulfated derivative (6-sulfate, 6S). Moreover, the 23-S product completely inhibited the infection of AIDS virus to T lymphocytes at concentrations as low as 0.28 microgram/mL without significant cytotoxicity. The regioselective introduction of sulfate group(s) at O-2 and/or O-3 had little effect on generating anticoagulant activity, whereas 6-O-sulfated chitin strongly inhibits blood coagulation. These results suggest that the specific interaction of these new types of chitin sulfates with gp 120 of the AIDS virus depends significantly on the sites of sulfation rather than on the total degree of substitution on sugar residues.
本文描述了一种新颖且便捷的方法，用于几丁质和壳聚糖硫酸化类似物的区域选择性合成，该方法与结构-生物活性研究相关。已发现壳聚糖的完全保护的可溶性衍生物是合成一类新型硫酸化多糖的有用中间体，即2-乙酰氨基-2-脱氧-3-O-磺基-(1→4)-β-D-吡喃葡萄糖聚糖（3-硫酸盐，3S，4）和(1→4)-2-脱氧-2-磺酰胺基-3-O-磺基-(1→4)-β-D-吡喃葡萄糖聚糖（2,3-二硫酸盐，23-S，3）。对这些化合物进行了以下活性测试：（i）体外抑制HIV-1复制；（ii）抑制血液凝固。结果表明，在O-2和/或O-3处的选择性硫酸化产生了有效的抗逆转录病毒药物，其对艾滋病病毒体外感染的抑制作用比已知的6-O-硫酸化衍生物（6-硫酸盐，6S）高得多。此外，23-S产物在低至0.28微克/毫升的浓度下就能完全抑制艾滋病病毒对T淋巴细胞的感染，且无明显细胞毒性。在O-2和/或O-3处区域选择性引入硫酸基团对产生抗凝血活性影响不大，而6-O-硫酸化几丁质强烈抑制血液凝固。这些结果表明，这些新型几丁质硫酸盐与艾滋病病毒gp 120的特异性相互作用很大程度上取决于硫酸化位点，而非糖残基上的总取代度。
