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基于海洋来源的活性吲哚生物碱的发现,功能导向合成以及对糖尿病靶点PTP1B的选择性抑制活性研究

批准号41676073 学科分类海洋化学 ( D0602 )
项目负责人李序文 负责人职称副研究员 依托单位中国科学院上海药物研究所
资助金额64.00
万元
项目类别面上项目 研究期限2017 年 01 月 01 日 至
2020 年 12 月 31 日
中文主题词海洋吲哚生物碱;化学生态学;功能导向合成;PTP1B抑制剂;糖尿病
英文主题词Marine indole alkaloids;Chemical ecology;Function oriented synthesis;PTP1B inhibitors;Diabetes

摘要

中文摘要 Phidianidines是本组从中国南海软体动物Phidiana militaris中获得结构新颖罕见的含1,2,4-噁二唑环的吲哚生物碱类活性天然产物。截至目前,尚没有任何其它关于该软体动物的化学成分及phidianidine类天然产物发现的报道,而申请人对该类化合物的结构改造发现了其具有选择性抑制糖尿病靶点PTP1B的活性,值得深入研究。因此,本项目以phidianidine为出发点,一方面在化学生态学角度从该软体动物及其捕食海绵中寻找更多类似活性吲哚生物碱,另一方面重点对该类化合物在构效关系和作用机制分析的基础上引入包括双环[x,y,z]烷基在内的功能基团进行进一步功能导向结构优化,最后对获得的所有化合物聚焦于PTP1B的选择性抑制活性筛选及作用机制评价,以期获得新型基于PTP1B靶点抑制的抗糖尿病药物先导化合物。本项目对糖尿病的靶向治疗和海洋资源的合理开发利用具有重要意义。
英文摘要 Phidianidines are novel indole alkaloids with an uncommon 1,2,4-oxadiazole ring, which have been isolated from the marine opisthobranch mollusk Phidiana militaris. Up until now, there is no other report on the chemical investigation of P. militaris and the discovery of phidianidine-like indole alkaloids from marine sources. We previously did the structure modification and biological investigation of phidianidines, leading to the discovery of a series of small molecules of diabetes targeted PTP1B inhibitory activities, which is promising for further study towards anti-diabetes drugs. Hence, this project would take phidianidines as a starting point, on one hand to search for more phidianidine-like alkaloids from P. militaris and its prey sponge Smenospongia sp. in view of their chemical and ecological relationship; on the other hand to highlight on the function oriented synthesis of such molecules by introducing functional groups such as bicyclo[x,y,z]alkanes on the basis of the structure-activity relationship and bioactive mechanism studies; finally to focus on the investigation of selective PTP1B inhibitory activities towards novel specific lead compounds of PTP1B inhibitors for the treatment of diabetes. This project is significant for the targeted treatment of Diabetes and the rational utilization of marine sources.
结题摘要

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