Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/Profesor García González 1, 41012 Seville, Spain.
Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, 18016 Granada, Spain.
Molecules. 2019 Aug 8;24(16):2882. doi: 10.3390/molecules24162882.
The unique stereoelectronic properties of sp-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp-iminosugar conjugates, the sp-iminosugar glycolipids (sp-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure-activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective -allylation followed by thiol-ene "click" coupling provides a very convenient access to α--glycoside sp-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp-iminosugar precursors with different configurational profiles (d- or d- in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly α-glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.
sp-亚氨基糖的独特立体电子性质使其能够参与糖苷化反应，从而成为真正的碳水化合物化学模拟物。在 sp-亚氨基糖缀合物中，sp-亚氨基糖糖脂（sp-IGL）表现出多种有趣的药理特性，从糖苷酶抑制作用到抗增殖、抗寄生虫和抗炎活性。因此，开发与分子多样性导向策略相兼容的策略以进行构效关系研究是非常需要的。在这里，我们展示了一个反应序列，包括立体选择性的 -烯丙基化反应，然后是硫醇-烯“点击”偶联反应，为α--糖苷 sp-IGL 的合成提供了非常方便的途径。通过使用具有不同构型（在本工作中为 d-或 d-）的 sp-亚氨基糖前体以及不同的硫醇，以及对硫醚加成物进行氧化（在本工作中为相应的砜），可以对糖基部分和糖苷配基尾部进行修饰。以这种方式制备了一系列衍生物，并在不同条件下评估了它们的糖苷酶抑制、抗增殖和抗利什曼原虫活性。结果证实，糖苷酶的抑制，特别是α-葡萄糖苷酶的抑制，与抗肿瘤/杀利什曼原虫活性无关。这些数据也与后两种活性一致，即 sp-IGL 能够以依赖细胞系和细胞背景的方式干扰免疫系统的反应。
