喜树碱N-乙酰二肽和甘氨酸酯衍生物合成及体外活性筛选

发布时间：2018-04-01 10:23

本文选题：喜树碱　切入点：半合成　出处：《东北林业大学》2014年硕士论文

【摘要】：喜树碱(Camptothecin, CPT)是从中国喜树(Camptotheca acuminata)中分离得到的天然生物碱,由于具有较强的抗肿瘤活性和独特的拓扑异构酶抑制机制而受到了广泛的关注。喜树碱E环的内酯结构极易断裂而产生强的毒性。本研究旨在20(S)-OH上引入取代基团以增强内酯结构稳定性,降低喜树碱的毒副作用。在喜树碱20位引入N-乙酰二肽酰和N端不同酰胺基保护的甘氨酰得到一系列喜树碱酯类衍生物,另外还在甲氧基喜树碱20位引入N-乙酰氨基酰得到两种衍生物；利用核磁共振和质谱等分析方法进行了结构鉴定。采用MTT法进行体外抗肿瘤活性筛选,结果表明所合成的新化合物对人卵巢癌细胞系(2774)、人前列腺癌细胞系(DU145)、人胰腺癌细胞系(MPC2)均有良好的抑制活性。与母体化合物相比,大部分衍生物的体外抗肿瘤活性均有所降低,但化合物13体外细胞毒活性优于母体化合物,化合物4、8、12、14的抗肿瘤活性则与母体化合物CPT相当；除化合物14、16、17外,其它衍生物对于人前列腺癌细胞系毒性也有所降低；对人卵巢癌细胞系2774,化合物12、13、14的体外活性比母体化合物略差,化合物17的体外活性则优于母体化合物HCPT。所合成的化合物可进一步用于体内安全性评价。
[Abstract]:Camptothecin (CPT) is a natural alkaloid isolated from Camptotheca acuminata. it has attracted wide attention because of its strong antitumor activity and unique topoisomerase inhibition mechanism.The lactone structure of camptothecin E ring is easy to break and produce strong toxicity.The aim of this study was to introduce substituents into 20(S)-OH to enhance the structural stability of lactones and to reduce the toxicity and side effects of camptothecin.A series of camptothecin derivatives were obtained by introducing N-acetyldipeptidyl and N-terminal glycosyl protected at the 20 position of camptothecin, and two derivatives were obtained by introducing N-acetyl aminoacyl at the 20 position of methoxycamptothecin.The structure was identified by nuclear magnetic resonance (NMR) and mass spectrometry (MS).MTT assay was used to screen the antitumor activity in vitro. The results showed that the new compounds had good inhibitory activity against human ovarian cancer cell line, human prostate cancer cell line DU145and human pancreatic cancer cell line MPC2.The in vitro antitumor activity of most derivatives was lower than that of the parent compound, but the cytotoxic activity of compound 13 was superior to that of the parent compound.The synthesized compounds can be further used to evaluate the safety in vivo.
【学位授予单位】：东北林业大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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