【作者】 肖琼；

【导师】 谢平； 尹大力； 俞晓明；

【作者基本信息】 中国协和医科大学 ， 药物化学， 2009， 硕士

【摘要】 Largazole是从弗罗里达的海洋蓝藻Smploca sp.中分离得到的具有十六元环肽内酯结构的HDACs抑制剂,它能够选择性抑制癌细胞的生长。该天然产物骨架结构新颖,其结构包括:4-甲基取代的二氢噻唑环与噻唑环的偶联部分,L-缬氨酸和（3S,4E）-3-羟基-7-巯基-4-庚烯酸。本论文采用“最少保护策略”研究了Largazole的全合成,并通过4-甲基取代的二氢噻唑环与噻唑环的偶联反应,以Nagao Evans辅剂诱导的不对称Aldol反应,苄基取代的四氢噻唑硫酮与羰基形成的活性酰胺直接与偶联片段上的氨基发生的氨交换反应,以及大环内酰胺的合成等关键步骤,成功完成了该天然产物的全合成。合成的天然产物Largazole的结构,经¹H-NMR,¹³C-NMR,EI-MS谱确定,与文献报道的天然产物数据一致。此外,本论文以Largazole为先导化合物,设计出两个结构简化物。目前,其合成工作正在进行。更多还原

【Abstract】 Largazole is a cyclic depsipeptide, isolated from a cyanobacterium of Floridian marine cyanobacterium Symploca sp.. This compound exhibited potent growth-inhibitory activety in several cancer cell lines. It possesses a dense combination of unusual structural features, including a substituted 4-methylthiazoline fused to a thiazole, L-valine and （3S,4E）-3-hydroxyl-7-thio-4-heptenoic acid. The thesis described less-protection synthesis of Largazole, in which the key steps included thiazoline-thiazole formation, the use of the Nagao thiazolidinethione auxiliary for a diastereoselective actetate aldol reaction, the amino-exchange reaction of the amino of thiazoline-thiazole derivative and active amide which was formed with Nagao thiazolidinethione and carbonyl, and macrolactamization. The molecular structure of the product was determined by ¹H-NMR, ¹³C-NMR, ESI-MS and was found to be consistanted with reported data. In addition, we also design and synthesize two analogs of Largazole.更多还原