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抗肿瘤活性肽YSL、YSV及其C端衍生物的反向固相合成
Inverse Solid Phase Synthesis of Antitumor Peptide YSL、YSV and C-terminal Derivatives
【作者】 陈雷；
【作者基本信息】 山东大学 ， 药学（专业学位）， 2014， 硕士
【摘要】 YSL、YSV是通过高通量筛选而来的两个具有抗肿瘤活性的三肽。两者结构相似,但抗肿瘤活性不同,YSL具有抗肝癌活性,YSV具有抗非小细胞肺癌与黑色素瘤活性,所以可考虑替换第三个氨基酸以寻求其它活性三肽。本论文将多肽固相合成中应用最广泛的Fmoc法与转移活化酯技术结合,通过探索,优化各步反应条件,改进传统的叠氮法,引入高效偶联试剂HOCt,建立了肽链由N端向C端延长及肽链C端修饰的新方法：反向固相合成法(Inverse Solid Phase Peptide Synthesis, ISPPS)。该方法室温进行,反应条件温和,过程易于监测,后处理简单高效,与正向固相合成互补,可高效地实现肽链延长以及C端修饰。论文具体开展的工作主要包括四部分：(1)探索恰当的方法,合成适用于ISPPS的氨基酸原料；(2)设计并合成合理的Linker,连接王树脂与肽链的N端；(3)利用所建立的方法,高效简捷地合成了抗肿瘤活性肽YSL、YSV及其结构类似物YSA、YSI、YSF与各种C端衍生物,并以HP-LC及MS进行纯度与结构认证；(4)MTT法对所合成的部分YSL结构类似物进行初步的活性测试。
【Abstract】 YSL and YSV are two anti-tumor tripeptides obtained through high throughput screening. They have similar structures but different anti-tumor activity. YSL has potent Anti-hepatoma activity while YSV can strongly inhibit non-small cell lung cancer and Melanoma, so we consider modifying the third amino acid to synthesize new tripeptides with better anti-tumor activity.The thesis combines the advantages of Fmoc-SPPS and TAEC technology.By exploring and optimizing reaction conditions, improving traditional azide method and introducing high efficient coupling reagent HOCt, we developed a new method (Inverse Solid Phase Peptide Synthesis, ISPPS) to modify C-terminal of peptide and synthesize peptide from N terminal to C terminal. The reaction can be carried out at room temperature under mild conditions and be easily monitored, and the working-up is simple and efficient. This method is complementary to the direct solid phase peptide synthesis.Four parts of work were done in this thesis:(1) Explore appropriate methods to synthesize amino acids materials of ISPPS;(2) Design and synthesize rational linker to connect the Wang resin and N-terminal of peptide chain;(3) Synthesize anti-tumor peptide YSL, YSV and its derivatives YSA, YSI, YSF as well as all kinds of C-terminal derivatives by ISPPS in a simple and efficient way. All the compounds we synthesized have been confirmed by HPLC and MS.(4) Evaluate biological activity of several YSL derivatives by MTT method preliminarily.