The heparan sulfate mimetic PI-88 is a complex mixture of sulfated oligosaccharides with anti-metastatic and anti-angiogenic activity due to its potent inhibition of heparanase and heparan sulfate-dependent angiogenic growth factors. It was recently in Phase III clinical trials for postresection hepatocellular carcinoma. The major oligosaccharide constituents of PI-88 were prepared for the first time by sulfonation of individually purified phosphorylated oligosaccharides isolated from the PI-88 precursor. PI-88 and its components were subjected to detailed 1D and 2D NMR spectroscopic analysis. The spectra of the individual components greatly assisted the assignment of minor resonances in the ¹H NMR spectrum of PI-88. The data also showed that the majority of the oligosaccharides in PI-88 are fully sulfated and that undersulfated species present are largely due to anomeric desulfation. The solution conformation of the phosphomannopentaose sulfate (major component) of PI-88 was then determined by a combination of molecular dynamics simulations and NOE measurements which may provide insights into its binding interactions with target proteins.

中文翻译：

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硫酸乙酰肝素模拟物PI-88的结构和构象研究

硫酸乙酰肝素模拟物PI-88是硫酸化寡糖的复杂混合物，由于其对乙酰肝素酶和硫酸乙酰肝素依赖性血管生成生长因子的有效抑制作用，因此具有抗转移和抗血管生成活性。它最近在切除肝细胞癌的III期临床试验中。通过磺化从PI-88前体分离的单独纯化的磷酸化低聚糖，首次制备了PI-88的主要低聚糖成分。对PI-88及其组件进行了详细的1D和2D NMR光谱分析。各个成分的光谱极大地协助了¹中较小共振的分配。PI-88的1 H NMR谱。数据还显示，PI-88中的大多数寡糖已被完全硫酸化，而存在的亚硫酸根物质主要是由于异头脱硫作用。然后，通过分子动力学模拟和NOE测量的组合来确定PI-88的磷酸磷酸甘露戊糖（主要成分）的溶液构象，这可能会提供有关其与靶蛋白的结合相互作用的见解。