Synthesis of thrombin-inhibiting heparin mimetics without side effects
Synthesis of thrombin-inhibiting heparin mimetics without side effects
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DOI：
10.1038/18877
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发表时间：
1999-04-01
期刊：
影响因子：
64.8
通讯作者：
Herbert, JM
中科院分区：
文献类型：
--
作者：
Petitou, M;Hérault, LP;Herbert, JM
药理活性化合物的不良副作用通常可以通过结构修饰消除。但多糖肝素复杂的异质结构(1)限制了这种方法的破碎性，导致低分子质量肝素制剂的耐受性稍好(2)。尽管有这种改善，肝素诱导的血小板减少症（HIT），与血小板因子4 （PF4）的相互作用有关，在较小程度上，出血(4)，仍然是肝素治疗的显著副作用。寡糖化学的突破(5)使得肝素五糖抗凝血酶结合位点的全合成成为可能（6,7）。这种五糖代表了一种新的潜在抗血栓药物家族，缺乏凝血酶抑制特性，并且与血液和血管成分无不良相互作用。为了获得更有效和耐受性良好的抗血栓药物，我们希望合成能够抑制凝血酶的肝素模拟物，即较长的低聚糖。像凝血酶抑制一样，不希望的相互作用与分子的电荷和大小直接相关(8)，因此我们必须设计能够区分凝血酶和其他蛋白质的结构，特别是PF4。在这里，我们描述了使用多步聚合合成来获得满足这些要求的硫酸低聚糖。
Unwanted side effects of pharmacologically active compounds can usually be eliminated by structural modifications. But the complex heterogeneous structure of the polysaccharide heparin(1) has limited this approach to fragmentation, leading to slightly better-tolerated heparin preparations of low molecular mass(2). Despite this improvement, heparin-induced thrombocytopaenia(3) (HIT), related to an interaction with platelet factor 4 (PF4) and, to a lesser extent, haemorrhages(4), remain significant side effects of heparinotherapy. Breakthroughs in oligosaccharide chemistry(5) made possible the total synthesis of the pentasaccharide antithrombin-binding site of heparin(6,7). This pentasaccharide represents a new family of potential antithrombotic drugs, devoid of thrombin inhibitory properties, and free of undesired interactions with blood and vessel components. To obtain more potent and well-tolerated antithrombotic drugs, we wished to synthesize heparin mimetics able to inhibit thrombin, that is, longer oligosaccharides. Like thrombin inhibition, undesired interactions are directly correlated to the charge and the size of the molecules(8), so we had to design structures that were able to discriminate between thrombin and other proteins, particularly PF4. Here we describe the use of multistep converging synthesis to obtain sulphated oligosaccharides that meet these requirements.