摘 要

2-疏基-1-甲基咪唑（MMI）是用于治疗甲状腺功能亢进的主要药物，然而，由于它伴随有肺癌，肾脏和肝脏损害，诱发肝毒性患者出现疲劳，瘙痒和不适症状。这些缺点会影响它在临床中的应用。为了改善MMI的这些缺陷，本文中我们首先以MMI为原药，与丙炔酸（PA）进行Michael加成反应制得中间体MMI -PA，然后与十八醇（St OH）的末端羟基反应制得两亲性谷胱甘肽（GSH）刺激响应的2-疏基-1-甲基咪唑前药MMI -PA-St ，然后利用其两亲性特征在水溶液中自组装形成前药胶束。我们希望制得的前药胶束通过经皮给药作用于甲状腺位点，并响应细胞内GSH刺激释放MMI，以降低药物的毒副作用。主要的工结论总结如下：

1. 两亲性MMI -PA-St前药的合成及表征：

首先，以MMI与丙炔酸（PA）为原料制备得中间体MMI -PA；然后通过该分子上的羧基与十八醇的末端羟基反应，制得两亲性前药MMI -PA-St；最后，采用红外、核磁表征确证了MMI，MMI -PA及MMI -PA-St前药的化学结构。

1. 以制备的MMI -PA-St前药为原料制备MMI -PA-St前药胶束，并探究其谷胱甘肽敏感特性。利用纳米粒度和Zeta电位仪测定MMI -PA-St前药胶束溶液在不同浓度的GSH处理前后胶束粒子的平均粒径(MD)及多分散系数(PDI)，探究谷胱甘肽(GSH)敏感响应，实验结果表明，MMI -PA-St前药胶束在低浓度的谷胱甘肽溶液中，平均粒径（MD）及多分散系数（PDI）随着时间的改变并未发生太大改变，而高浓度GSH溶液处理后，其MD及PDI值均发生明显变化。证明了MMI -PA-St前药胶束具有明显的谷胱甘肽敏感性。
2. GSH响应的MMI -PA-St前药胶束释药研究：考察不同GSH浓度下MMI -PA-St前药胶束的MMI释放情况。实验结果表明，MMI的释放与GSH浓度线性相关。与微摩尔浓度的GSH刺激相比，毫摩尔浓度GSH刺激下的MMI -PA-St前药胶束释药率更高。

关键词：2-疏基-1-甲基咪唑（MMI）；前药；MMI -PA-St前药胶束；谷胱甘肽敏感；释药

Abstract

2-silyl-1-methylimidazole (MMI) is a major drug for the treatment of hyperthyroidism,however, because it is accompanied by lung cancer, kidney and liver damage,induced liver toxicity in patients with fatigue, itching and discomfort symptoms.These shortcomings can affect its application in clinical practice.In order to improve these defects of MMI, in this paper,the MMI -PA was prepared by Michael addition reaction with propionic acid (PA) with MMI as the original drug and then reacted with terminal hydroxyl groups of octadecyl alcohol (St OH),Preparation of amphiphilic glutathione (GSH) stimulated response of 2-silyl-1-methyl imidazole pro drug MMI -PA-St,and then use its amphiphilic characteristics in aqueous solution self-assembly to form pro drug micelles.We hope that the pro drug micelles act on the thyroid site by transdermal administration and affect the release of MMI by intracellular GSH stimulation to reduce the side effects of the drug. The main work and conclusions are summarized as follows:

I. Synthesis and characterization of amphiphilic MMI -PA-St pro drugs:

Firstly, MMI -PA was prepared from MMI and propionic acid (PA),and then through the molecular carboxyl group and octadecyl alcohol terminal hydroxyl group reaction, obtained amphiphilic pro drug MMI -PA-St;Finally, the chemical structure of MMI, MMI -PA and MMI -PA-St pro drug was confirmed by IR and NMR.

II.The MMI -PA-St pro drug micelles were prepared by preparative MMI -PA-St pro drug and the glutathione- sensitive properties were explored:

The micellar solution of MMI PA-St pro drug was determined by nano-particle size and Zeta potentiometer. Before and after treatment with different concentrations of GSH.The average particle size (MD) and polydispersity (PDI) of micelles,to explore the sensitive response of glutathione (GSH), the experimental results show that,MMI -PA-St pro drug micelles in low concentrations of glutathione solution.The average particle size (MD) and the polydisperse coefficient (PDI) did not change much with time,While the high concentration of GSH solution, the MD and PDI values were significantly changed.It was proved that the micelles of MMI -PA-St pro drug had obvious glutathione sensitivity.

III. GSH response of the MMI- PA-St pro drug micelles drug release study:

To investigate the release of MMI in the micelles of MMI-PA-St prodrugs at

different concentrations of GSH.The results showed that the release of MMI was linearly related to GSH concentration.Compared with the micro-molar concentration of GSH stimulation,The release rate of MMI -PA-St pro drug was significantly higher under the stimulation of MTH.

Key words: 2-silyl-1-methylimidazole (MMI); pro drug; MMI -PA-St pro drug micelles; glutathione sensitive;

目 录

第一章 绪论..................................................................................................................1

1.1 引言.....................................................................................................................1

1.2 刺激响应型两亲性小分子前药.........................................................................1

1.3 MMI在治疗甲亢中的应用.................................................................................2

1.4 文章的基本思想和主要研究内容.....................................................................3

第二章 GSH响应的2-疏基-1-甲基咪唑前药的合成及表征.....................................4

2.1 引言.....................................................................................................................4

2.2 实验部分.............................................................................................................5

2.2.1 仪器与材料..................................................................................................5

2.2.2 中间体MMI -PA的制备.............................................................................6

2.2.3 MMI对比试验..............................................................................................6

2.2.4 MMI -PA-St前药的制备..............................................................................7

2.2.5 MMI -PA及MMI -PA-St的结构表征..........................................................7

2.3 结果与讨论.........................................................................................................7

2.3.1 MMI -PA和MMI -PA-St的制备..................................................................7

2.3.2 核磁光谱分析..............................................................................................9

2.4 小结...................................................................................................................10