【作者】 李远志；

【导师】 徐亮；

【作者基本信息】 四川大学 ， 天然药物化学， 2021， 硕士

【摘要】 喜树碱(camptothecin)是Wani和Wall等从中国特有植物-喜树(Camtoptheca acuminata)中率先分离得到的一种天然抗肿瘤生物碱。其作用机制是通过与肿瘤细胞中高度活跃的拓扑异构酶I特异性结合并抑制其活性,从而引起DNA双链断裂,最终导致肿瘤细胞凋亡。目前以喜树碱作为先导化合物开发上市的喜树碱类似物有四个,包括伊立替康(Irinotecan)、拓扑替康(Topotecan)、贝洛替康(Belotecan)以及与单克隆抗体偶联的德鲁替康(Deruxtecan)。虽然目前已经报道了众多各具特色的喜树碱合成路线,但其中大部分仍然存在路线较长、合成效率低、不易制备衍生物、或规模合成成本昂贵等问题。本课题研究针对上述问题,在生源合成的启发下发展了一条高效简洁的仿生无保护基合成喜树碱的新路线。该路线以色胺和方便易制的乙基戊烯二醛盐为起始物,经Pictet-Spengler反应、氧杂Diels-Alder反应以及Winterfeldt仿生氧化等关键反应,以总共7步25%的收率实现了喜树碱的形式合成。并在此基础上,更换5-甲氧基色胺为起始物,进一步实现了10-甲氧基喜树碱的形式合成。同时我们还利用路线中C-7位三氟磺酰酯取代的喹啉中间体合成了两个C-7位乙基取代的喜树碱类似物。该路线不仅提供了一种更为简洁的生源模式合成喜树碱的方法,也为进一步制备AB环或E环的喜树碱衍生物以及相应构效关系的研究奠定了良好的基础。更多还原

【Abstract】 Camptothecin is a natural anti-tumor alkaloid,which was originally isolated from Camptothecin acuminate(Xi Shu,originating in China)by Wani and Wall.Its anticancer mechanism is specifically binding to topoisomerase I,which is highly active in tumor cells,and inhibiting its activity,thus causing DNA double strand break and leading to tumor cell apoptosis.There are currently four camptothecin analogues with camptothecin as the lead compound developed and marketed,including irinotecan,topotecan,belotecan and deruxtecan.Although many unique synthetic routes of camptothecin have been reported,most of them still have some problems,such as multiple steps low synthesis efficiency,difficult preparation for derivatives,or high cost of large-scale synthesis etc.In response to the above-mentioned problems,we have developed a concise biogenetically inspired formal synthesis of camptothecin without using of protecting groups.The formal synthesis of camptothecin starts from tryptamine and easily prepared ethyl pentylene dialdehyde salt,and undergoes key reactions such as Pictet-Spengler reaction,oxa-Diels-Alder reaction,and Winterfeldt biomimetic oxidation with a total yield of 25% in 7 steps.On this basis,replacing5-methoxytryptamine as the starting material,further realized the formal synthesis of 10-methoxycamptothecin.At the same time,we synthesized two C-7 ethyl substituted camptothecin analogues by using the C-7 trifluorosulfonyl ester substituted quinoline intermediate in the route.This route not only provides a more concise method for the synthesis of camptothecin in the biogenic mode,but also lays a good foundation for further preparation of AB or E ring camptothecin derivatives and corresponding structure-activity relationship researches.更多还原