以γ-及δ-内酰胺糖为原料的新型并多杂环糖的合成及生物活性研究

This project is committed to the novel synthesis of the analogues of the natural products possessing important biological activities such as anticancer, antidepressant, antilishmania, anti cone worm, and antimuscarinic. These analogues are heteropolycycle fused aza-sugars, which are efficiently synthesized from structurally diverse sugar γ- and δ-lactams. Then their biological activities are tested, based on which the next generation of analogues are designed, synthesized and evaluated. In this way, the lead compound for creation of innovative medicine or the new chemical entity for the drug discovery is expected to be obtained.. (1) The natural product (S)-desbromoarborescidine A, isolated from Dracontomelum mangiferum, possesses a broad spectrum of anticancer and antidepressant activities. Another natural product (S)-harmicine, isolated from Kopsia griffithii, has anticancer and antilishmania activities. A series of analogues of (S)-desbromoarborescidine A are initially synthesized from various sugar δ-lactams, and their anticancer and antidepressant activities are tested. Based on the results, the next generation of analogues are designed, synthesized, and the biological activities are evaluated again. In this way, the lead compound on the basis of sugar δ-lactam and (S)-desbromoarborescidine A scaffold is obtained. Similarly, the analogues of (S)-harmicine are synthesized from various sugar γ-lactams, and their anticancer and antilishmania activities are tested. The lead compound on the basis of sugar γ-lactam and (S)-harmicine scaffold for creation of innovative anticancer medicine is expected to be obtained.. (2) Two series of tetrahydroquinoline fused aza-sugars are synthesized from various sugar δ- and γ-lactams, respectively. They are the respective analogues of the natural products (-)-pessoine and gephyrotoxin which possess anti cone worm and antimuscarinic activities. The biological activities of the analogues are evaluated. Then the new analogues are designed according to the biological data and evaluated once again. Thus, the lead compound is expected to be acquired on account of sugar and the scaffold of (-)-pessoine or gephyrotoxin.. (3) Various dihydroquinoline fused aza-sugars, including their quinoxaline and 2H-imidazol-2-one(thione) fused derivatives are synthesized from structurally diverse sugar lactams. The anticancer activity of these compounds and their heteropolycycle derivatives is tested, based on which the new analogs are designed, synthesized, and then the anticancer activity is evaluated. The new chemical entity or lead compound for creation of innovative anticancer medicine is expected to be acquired on the basis of dihydroquinoline fused aza-sugar.

以γ-及δ-内酰胺糖为原料，建立简洁高效的合成新方法，合成结构新颖的并多杂环糖类生物活性天然产物类似物；配合生物活性测试，获得结构新颖、基于糖和天然产物骨架的创新药物先导化合物或化学实体。（1）构筑具有广谱抗癌、抗抑郁活性天然产物(S)-desbromoarborescidine A的骨架，合成其系列类似物；按类似路线，合成具有抗肿瘤、抗利什曼原虫活性天然产物(S)-Harmicine的系列类似物；（2）构筑具有抗锥虫活性天然产物(-)-pessoine的骨架，合成其系列类似物；按类似路线，合成具有抗毒蕈碱活性天然产物gephyrotoxin的类似物；（3）合成具有潜在抗癌活性的二氢喹啉并氮杂糖及其并多杂环系列化合物。将上述类似物进行相应的生物活性测试，根据测得的活性数据，再设计新一代类似物，再进行生物学评估…，从而获得结构新颖、基于糖和天然产物骨架的创新药物先导化合物或化学实体。

将生物活性有利的杂环和糖的结构多样性、手性结合起来，合成生物活性杂环糖类天然产物及其类似物，是发现先导化合物的有效方法之一。杂环与糖环稠合而形成的并杂环糖，广泛存在于自然界中，有些具有重要的生物活性。因此，建立高效合成方法，合成这类化合物，是获得创新药物先导化合物或生物活性化学实体的有效手段。. 以γ-和δ-内酰胺糖为基本原料，以适用于糖化学反应要求的温和反应为指导，发展了合成新方法，沿糖环C-N键构筑并杂环体系，合成了多种并多杂环化合物。（1）分别以δ-内酰胺糖以及γ-内酰胺糖为原料，在糖环上通过炔的氧化、苯环胺化、吲哚环的形成等几步主要反应，构建了一系列吲哚环与糖环并合的多环化合物，这些化合物是具有抗癌、抗抑郁活性天然产物(S)-desbromoarborescidine A的类似物。（2）以δ-内酰胺糖为原料，在糖环上通过选择性Sonogashira反应、炔键彻底加氢还原、苯环胺化等主要反应，将新生成的四氢喹啉环、六元环氮杂糖并合于同一分子，合成三环亚胺糖。按照同样合成路线，以γ-内酰胺糖为原料，将新生成的二氢喹啉环、五元环氮杂糖并合于同一分子，合成另一类三环亚胺糖。（3）在上述合成 desbromoarborescidine A 类似物过程中，得到了一系列邻二酮中间体。以该中间体为原料，使其与邻苯二胺反应，再经过还原、脱保护基等步骤，得到一系列喹喔啉并多杂环糖。. C-核苷及其类似物分子中，碱基或杂环通过C—C键与糖基相连接。这种C—C键不同于普通核苷分子中的C—O或C—N苷键，它对水解酶稳定，从而能使C-核苷分子与其DNA或RNA合成酶作用，因此表现出抗菌，抗病毒，抗癌等广谱生物学活性。我们以糖炔为基本原料，开发了合成新方法，合成了咪唑C-核苷类似物、糖基单取代及双取代的噻吩C-核苷类似物以及吲哚C-核苷类似物。这些化合物都是生物活性天然C-核苷的类似物。. 对上述部分化合物进行了生物活性研究，其中一些化合物有良好的抗肿瘤活性。抗病毒活性研究正在进行中。