基于氟代亚氨基糖的糖苷酶抑制剂的设计、合成与活性研究

Bicyclic iminosugars have shown important applications in pharmaceutical industry due to their powerful bioactivities against various diseases including HIV and cancer. In order to pursue lead compounds with desired biological activities, structural modification analogues of bicyclic iminosugars must be designed and developed, among which fluorinated and branched derivatives have also become important and effective tools of structure-activity relationship (SAR) study. Since the existing synthetic strategies for fluorinated bicyclic iminosugars suffer from drawbacks such as poor selectivity, low yield and rearrangement, efficient and highly-selective synthetic methods would be developed in this project based on conformationally pre-fixed derivatives, fluorine-containing building blocks and asymmetric fluorination strategy to prepare fluorinated and structure-modified derivatives of a series of important bicyclic iminosugars. Biological activity study of these derivatives will help to clarify structure-activity relationship of bicyclic iminosugars and help to establish foundation for further design and development of novel bicyclic iminosugar lead compounds. This project aims at the following targets: fluorination reactivity study of iminosugar substrates, synthesis of B ring fluorinated and structure-modified derivatives of bicyclic iminosugars, synthesis of structure-modified B ring-open derivatives of bicyclic iminosugars, biological activities and structure-activity relationship (SAR) study of these iminosugars.

双环亚氨基糖已经在抗病毒与抗肿瘤相关的新药创制中显示出巨大的发展潜力。开展其合成方法研究，设计合成其衍生物，并系统研究此类化合物的构效关系有望发现高活性和高选择性的先导化合物。氟代与支化是最常用的结构修饰手段与考察构效关系的有效方法。针对现有双环亚氨基糖氟代衍生物的合成方法存在选择性差、收率低、易重排的问题，本课题将基于构象预固定策略、含氟砌块或不对称氟代策略，发展高效、高选择性的氟代双环亚氨基糖合成方法；完成一些重要双环亚氨基糖氟代与结构改造衍生物的设计与合成工作；建立一个具有分子多样性的双环亚氨基糖衍生物库；系统开展相关化合物的构效关系研究，为设计新型双环亚氨基糖类先导化合物提供依据。主要研究内容包括：亚氨基糖类底物的氟代反应性研究；双环亚氨基糖B环氟代与结构改造衍生物的合成；双环亚氨基糖B环开环衍生物的合成；亚氨基糖及其衍生物活性评价与构效关系研究。

双环亚氨基糖由于其特殊的分子骨架和重要生物活性已经在相关新药创制中显示出巨大的应用价值。发展此类化合物的结构修饰衍生物，并研究其构效关系，有望发现高活性和高选择性的先导化合物，并为进一步设计合成具有潜在药物活性的亚氨基糖化合物提供依据。本课题基于含氟砌块与不对称氟代策略，完成了多种骨架亚氨基糖类底物的氟代反应性研究；在此基础上，完成了一些重要天然产物的氟代衍生物库的构建；进一步开展了其B环以各类型取代基改造的衍生物以及开环衍生物的合成与化合物库构建；对所成的化合物进行了系统的糖苷酶抑制活性评价，结合分子对接研究，系统研究了相关双环亚氨基糖的构效关系，首次发现了一些氟参与的化合物与酶的新颖结合方式；在此基础上设计合成了一系列结构新颖的亚氨基糖衍生物，部分表现出超高或重要的糖苷酶抑制活性，有望在抗病毒、抗肿瘤以及糖尿病、高雪氏病及庞贝氏症等领域得到应用。本课题发展的催化不对称氟代策略对亚氨基糖具有广泛适用性，所阐明的构效关系对相关亚氨基糖药物的设计合成具有重要参考意义。

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