苦马豆素和地高辛氟代衍生物的合成与活性研究.pdfVIP

摘 要 氟代已经成为药物研发的常用手段之一，经过氟代修饰后的产物往往具有较 好的生物学活性。本论文主要包括两部分工作： 一、苦马豆素及其氟代衍生物的合成研究 苦马豆素是从灰苦马豆中分离出来的多羟基吲哚里西啶生物碱，同时也是高 尔基体α-甘露糖苷酶II 的强抑制剂,并具有显著的抗肿瘤活性，已经进入临床II 期研究。论文以148a 为关键的合成子，通过Barbier 反应、硼氢化氧化以及还原 胺化等步骤高效的完成苦马豆素及其差向异构体异构体的合成，并以同样的方法 完成了其对映体的合成。在此基础上完成了两个氟代产物的合成，该路线的发展 为后续苦马豆素氟代衍生化研究奠定了基础。 二 、2-氟代-2,6-二脱氧糖及氟代地高辛的合成及活性研究 含氟药物在临床治疗药物中占有相当比重，将氟原子或含氟基团引入到小分 子药物中, 是药物化学结构改造的重要研究策略之一。近年来氟代糖的研究也倍 受青睐，本课题完成了对2-氟代-2,6-二脱氧糖合成方法的探究，并合成了2-氟 代洋地黄毒糖和2-氟代-Cymarose 糖。并对该方法做了应用研究，完成了氟代地 高辛的合成工作后，通过活性测试我们发现氟代产物对A549 细胞的抑制活性比 地高辛降低近十倍，该工作对后续地高辛其他糖环单元的氟代工作有一定的参考 意义。 关键词：氟代，苦马豆素；2-氟代-2, 6-二脱氧糖，地高辛 I Abstract Fluorination has become one of the most used methods of drug research and development, and the products after structural modification often have better or different biological activities. This dissertation consists of two sections. 1、The synthesis of Swainsonine and its fluorinated derivatives Swainsonine, isolated from Swainsona canescens, is a potent inhibitor of Golgi mannosidase II and may be useful in the treatment of cancer and other diseases. In this dissertation, compound 148a was used as the key synthon, in the syntheses of swainsonine,its epimer and their corresponding enantiomers, with Barbier reaction, borohydride oxidation and reductive amination as key steps. Based on the successful synthesis of swainsonine, two fluorinated derivatives of the natural product were also synthesized, which laid a good foundation for the development of follow-up fluorinated derivatization of swainsonine. 2 、 Synthesis and activity of 2-fluoro-2,6-dideoxy sugar and fluorinated digoxin Fluorinated compounds comprise a substantial proportion in the therapeutic drugs. Introduction of fluorine or fluorinated substitutes is also an important strateg