【作者】 高远；

【导师】 林厚文；

【作者基本信息】 上海交通大学 ， 药学（专业学位）， 2019， 硕士

【摘要】 海绵是新药创制的源泉之一,是新型化学分子实体的宝库。其次生代谢产物种类繁多,化学结构极为丰富。在发现的新型海洋天然产物中,约有三分之一来源于海绵。Aaptamines是海绵中特有的一类生物碱,其具有独特的苯并[1,6]萘啶骨架,这类化合物具有良好生物活性,特别是在抗肿瘤方面。2014年我们课题组从南海海绵Aaptos aaptos中发现一系列C-3位胺基取代的aaptamine衍生物,并对其进行了活性筛选,结果显示包括3-（phenethylamino）demethyl（oxy）aaptamine（以下简称为PAAP）在内的多个化合物能够显著抑制肺癌干细胞活性,深入的药理机制研究证明PAAP能够靶向作用于Chk1激酶,抑制ATM/Chk1/Cdc25/C dc2信号通路,在与化疗药物顺铂联用时,能够取消化疗药物诱导的细胞周期阻滞,增加肺癌干细胞对化疗药物的敏感性。本论文以活性天然产物PAAP为目标,从商业购得的6,7-二甲氧基-异喹啉出发,先后尝试了多种构建aaptamine三元环方法,选取三个关键中间体进行尝试,最终通过新颖的钯催化还原环化和氢键参与的亲核加成-氧化串联等的7步反应,以20%以上的总收率实现了天然产物PAAP的全合成,并在此基础上进行结构改造,合成了一系列PAAP类似物。另外,本论文对天然产物Aaptamine进行了结构修饰,基于铃木反应等方法合成了30个C-3,C-7位芳香取代的衍生物。药理实验证明,结构改造工作显著提升了化合物的抗肿瘤活性,多个化合物对人乳腺癌MCF-7细胞、人宫颈癌Hela细胞、人肺癌H460细胞、白血病NB4细胞和淋巴瘤SNK-6细胞有较强抑制能力,IC₅₀值范围在0.6-10μM。更多还原

【Abstract】 Sponge is one of the sources of new drug creation and a treasure trove of new chemical molecular entities.Secondly,there are many kinds of raw metabolites and the chemical structure is extremely rich.About one-third of the new marine natural products found are derived from sponges.Aaptamines are a class of alkaloids unique to sponges that have a unique benzo[1,6]naphthyridine skeleton.These compounds have good biological activity,especially in anti-tumor.In 2014,our group discovered a series of amino acid substituted aaptamine derivatives at the C-3 position from the South Sea sponge Aaptos aaptos,and screened them for activity.The results showed that 3-（phenethylamino）demethyl（oxy）aaptamine(hereinafter referred to as Multiple compounds including PAAP can significantly inhibit lung cancer stem cell activity.Intensive pharmacological studies have demonstrated that PAAP can target Chk1 and inhibit the ATM/Chk1/Cdc25/Cdc2 signaling pathway when used in combination with the chemotherapy drug cisplatin.It can eliminate the cell cycle arrest induced by chemotherapy drugs and increase the sensitivity of lung cancer stem cells to chemotherapy drugs.In this paper,aiming at the active natural product PAAP,starting from the commercially available 6,7-dimethoxy-isoquinoline,various methods for constructing the aaptamine three-membered ring have been tried,and three key intermediates have been selected for experimentation.Finally,through the 7-step reaction of palladium-catalyzed reduction cyclization and hydrogen bonding,such as nucleophilic addition-oxidation series,the total synthesis of natural product PAAP is achieved with a total yield of more than 20%,and structural transformation is carried out on this basis.A series of PAAP analogs were synthesized.In addition,in this thesis,the natural product aaptamine was structurally modified,and 30 C-3,C-7 aromatic substituted derivatives were synthesized based on the Suzuki reaction.Pharmacological experiments have shown that the structural modification work significantly enhances the anti-tumor activity of the compounds.Several compounds have human breast cancer MCF-7 cells,human cervical cancer Hela cells,human lung cancer H460 cells,leukemia NB4 cells and lymphoma SNK-6cells.Strong inhibition,IC₅₀values range from 0.6-10μM.更多还原