Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88)
Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88)
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DOI：
10.1021/jm050618p
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发表时间：
2005-12-29
影响因子：
7.3
通讯作者：
Ferro, V
中科院分区：
文献类型：
--
作者：
Karoli, T;Liu, LG;Ferro, V
磷磺基甘露聚糖1（PI-88）是一种高度硫酸化的低聚糖混合物，目前正在癌症患者中进行临床评估。除了抗癌特性外，1还显示出许多其他有趣的生物活性。合成了一系列1的类似物，具有单碳（五糖）骨架，以便于结构表征和生物学结果的解释。以类似于1的方式，所有化合物都能够抑制乙酰肝素酶并与促血管生成生长因子FGF-1、FGF-2和VEGF紧密结合。该化合物还抑制单纯疱疹病毒（HSV-1）的细胞感染和细胞间传播。初步的药代动力学数据表明，与1相比，这些化合物显示出不同的药代动力学行为。特别值得注意的是正辛基衍生物，其清除速度比1慢3倍，可能增加全身暴露。
The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as it's anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.