新型核苷类似物的设计、合成和抗肿瘤活性研究

项目名称： 新型核苷类似物的设计、合成和抗肿瘤活性研究

项目编号： No.21202116

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机化学

项目作者： 郭翔海

作者单位： 天津大学

项目金额： 25万元

中文摘要： 核苷类化合物在抗肿瘤及抗病毒方面有着重要的作用，其化学及药物研究一直是医药界所关注的焦点。目前使用的核苷类抗肿瘤药物存在着耐药性（包括多药耐药性）的问题。另外，核苷类药物普遍存在毒副作用较大、吸收差和代谢快等缺点。本课题以具有抗肿瘤活性的天然核苷类物质克力托辛的结构为基础，采用计算机辅助药物设计的方法对克力托辛及其衍生物的活性进行归纳和总结，提出结构改造建议。结合已知核苷类药物齐多夫定（AZT）和硫代-phosphoramidite 的结构特点，设计出两个系列的新型克力托辛衍生物，制定合理的合成路线并合成这些化合物，探索其对于几种小鼠肿瘤细胞系和人癌细胞系的抗肿瘤活性。本研究可为具有独特2',3'-二脱氧-3'-叠氮基（氨基）糖基结构的新型克力托辛类似物提供合理的合成策略和方法；同时能为寻找、发现活性更强、作用更持久、毒性更低的肿瘤治疗药物提供新型药物分子实体以及开发参考建议。

中文关键词： 核苷类似物；克力托辛；合成；抗肿瘤药物；

英文摘要： Nucleosides are very important entities for development of antitumor and antivirus agents. The recent acceleration in the identification and characterisation of new molecular targets for cancer has focused considerable interest on the nucleoside chemistry and development of new anticancer agents from them. However, it has also been found that nucleoside drugs suffer from drug resistance(including mutidrug resistance). On the other hand, several disadvantages, including clinical toxicity, low absorption and fast metabolism are usually existing in current nucleoside drugs. With the aim of overcoming the drawbacks of nucleoside drugs, our research bases on structure and activity analyses of clitocine and its derivatives by computer-aided drug design, and several structure modifications are suggested to improve activity. Based on these suggestions, referred to the structure of antiviral drug AZT and design of the third generation antisense drugs thio-phosphoramidite, two series of new structural analogues of clitocine are designed. These new analogues will be synthesized, and whose antitumor activities against some tumor cell lines will be screened. Synthetic strategy and methods will be developed for the synthesis of unique 2',3'-dideoxy-3'-azo(amino) sugar type clitocine analogues, which could provide insights and

英文关键词： Nucleoside analogues；Clitocine；Synthesis；Antitumor drug；