基于官能糖的新型桥环型亚胺糖碳核苷类似物及其无环糖碳核苷中间体的合成研究

This project focuses on the development of concise and efficient routes for the novel syntheses of bridged C-nucleoside analogues of iminosugars by kneading sugars and heterocycles together. These analogues are conformationally restricted. Because sugar and heterocycle possess both structure and bioactivity diversity, and sugar is also optically pure substance, the combination of sugar and heterocycle with the chirality and the diversities into one molecule should produce potentially bioactive compound. The lead compounds for creation of innovative medicines and the new chemical entities in the drug discovery are expected to be obtained from the bridged C-nucleoside analogues of iminosugars synthesized by this method..The terminal alkyne sugars with -OH at C-5 or C-6 position are used as starting material, on which the heterocycle is firstly built from the functional group. The newly formed acyclic C-nucleoside analogues undergo cyclization to form iminosugar ring. Thus, the novel bridged C-nucleoside analogues of iminosugars are generated: (1) Various terminal alkyne sugars with -OH at C-5 or C-6 position are used to react with 2-iodo-6-(methoxymethoxy)benzenamine, followed by intramolecular nucleophilic addition, Mitsunobu reaction as the main steps to synthesize the analogues of the natural product Mitomycins having antitumor activity. After bioactivity testing, the next generation of the analogues are designed and synthesized. In this way, the lead compounds for the creation of innovative antitumor medicines will be obtained. (2) The terminal alkyne sugars mentioned above undergo Sonogashira reaction with acyl chlorides or 2-iodobenzamide, followed by reacting with hydrazine or intramolecular nucleophilic addition. 1H-pyrazole,isoindolin-1-one and isoquinolin-1(2H)-one are built on the sugars, respectively. Iminosugars are subsequently built by Mitsunobu reaction and three types of bridged C-nucleoside analogues of iminosugars are synthesized. In addition, a great many of acyclic C-nucleoside analogues are obtained as the intermediates.

项目拟将糖的手性，结构多样性，生物活性和杂环的结构多样性及生物活性揉合于同一分子中，发展合成新方法，合成结构新颖，糖环构象受限，具有潜在生物活性的桥环亚胺糖碳核苷类似物，从而获得结构新型创新药物先导化合物和化学实体。也就是以1，2位为炔基，5位或6位为游离羟基的各种官能糖为原料，借助糖的官能团，在糖分子中先后构建杂环和亚胺糖环，合成桥环型五元、六元环亚胺糖碳核苷类似物：（1）经4－5步常规化学反应合成具有抗肿瘤活性的天然产物Mitomycins的类似物，配合生物活性测试，获得基于糖和Mitomycins骨架的结构新颖创新抗肿瘤药物先导化合物。（2）经Sonogashira等3步常规反应在糖分子中先后分别构建吡唑，异吲哚啉酮，异喹啉酮等杂环和亚胺糖环，分别合成这类桥环型亚胺糖碳核苷类似物。在合成上述目标化合物的同时，得到一系列糖类无环碳核苷类似物，这些都为一类新药开发提供结构新颖的化学实体。

以官能糖为基本原料，发展合成新方法，合成了结构新颖，具有潜在生物活性的多种碳核苷类似物及桥环亚胺糖碳核苷类似物，通过抗肿瘤活性测试，部分化合物对多种癌细胞均表现出显著的细胞毒性。找到了抗肿瘤先导化合物。（1）以5、6位为游离羟基的各种端基炔糖为原料，建立了合成新方法，简捷高效合成了抗肿瘤活性天然产物Mitomycins的类似物，同时得到了一系列新型吲哚类无环碳核苷类似物。（2）以5、6位为游离羟基的端基炔糖为原料先后与酰氯，肼反应，再利用吡唑的NH与糖上一个游离羟基发生Mitsunobu反应构建亚胺糖环，建立了合成新方法，合成了一类桥环亚胺糖吡唑碳核苷类似物。（3）以炔糖为原料，使其与取代的邻碘苯甲酰胺经Sonogashira反应，分子内亲核加成反应构建异喹啉酮杂环，再经分子内Mitsunobu反应，建立了合成新方法，得到了一类桥环亚胺糖异喹啉酮碳核苷类似物。（4）将常见的廉价天然糖转化为糖基端基炔，以此为原料，开发合成新方法，得到了一系列（36种）芳基喹噁啉碳核苷类似物。（5）近期从板蓝根中发现了两种具有抗癌活性的吲哚碳核苷类似物，为了获得更多更好的抗肿瘤活性吲哚碳核苷类似物，选取9种糖基单炔和糖基双炔为原料，开发合成新方法，一锅两步反应合成了42种结构多样性的单吲哚和双吲哚碳核苷类似物。（6）Pyrazofurin是从Streptomyces candidus提取的天然产物，具有广谱抗肿瘤和抗病毒活性。选取10种结构多样性的炔糖，先后与各种酰氯，水合肼反应，开发了合成新方法，合成了一系列（64种）Pyrazofurin的吡唑碳核苷类似物。（7）以各种官能糖为原料，开发合成新方法，合成了47种嘧啶碳核苷类似物。（8）发现了室温快速高效制备邻二酮糖的新方法，将炔糖用n-Bu4NMnO4氧化，得到了56种结构新颖的邻二酮糖，氧化反应均可在数分钟内完成。（9）发现了二苯基氧化膦在 Mn(OAc)2•4H2O/空气作用下对烯糖2 位的区域和立体选择性自由基加成反应，提出并证实了反应机理，合成了一系列重要的 2 位二苯基氧膦取代的糖类化合物。

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