反式—左旋-1,2-环己二胺—环糊精键接物的设计、合成与结构表征

发布时间：2018-08-31 16:55

【摘要】：铂类抗肿瘤药物因其独特的作用机制、广泛的抗癌谱成为治疗恶性肿瘤的主要药物之一,但无靶向性、毒副作用、耐药性等问题成为了限制其扩大临床应用的障碍。超分子化学给药体系以其所具有的良好的安全性和低毒性近年来逐渐受到人们的关注。超分子大环化合物与铂类抗肿瘤配合物形成的包合物或键接物增强了铂类药物的水溶性、稳定性和安全性,并且因为具有潜在的肿瘤组织和器官靶向性成为了新型铂类抗肿瘤药物开发的一个热门的研究方向。环糊精作为第二代超分子大环化合物,目前被广泛的用于药物的构建与合成中。将铂类药物与环糊精结合形成的新型给药体系,其在抗肿瘤作用机制和细胞摄取机制上,不同于常规的铂类抗肿瘤药物,能克服经典铂类抗肿瘤药物具有的耐药性问题,利用大环化合物所具备的靶向药物转运能力,也能够降低传统铂类抗肿瘤药物的副作用。本文主要研究构建一系列环糊精-环己二胺键接物,以期作为新型铂类抗肿瘤药物的载体,从而克服目前铂类药物在治疗中所面对的诸多问题。同时,也将6-OTs-CD的制备进行了中试生产,并研究了利用酒石酸对混合的1,2-环己二胺进行拆分。本论文研究具体内容如下： 1、制备单-6-去氧-对甲苯磺酰基-p-环糊精(6-OTs-CD),并将其放大至中试生产,所得产物通过核磁共振氢谱进行了结构表征。 2、利用L/D-酒石酸对混合1,2-环己二胺进行化学手性拆分,分别分离出反式-R,R-1,2-环己二胺,反式-S,S-1,2-环己二胺和顺式-1,2-环己二胺。所得产物通过熔点测定,比旋光度测定确定其构型。 3、将6-OTs-CD进一步取代衍生,制备单-6-去氧-反式-R,R-1,2-环己二胺-p-环糊精(6-dach-CD)、单-6-去氧-甘氨酸-p-环糊精(6-Gly-CD)和单-6-去氧-琥珀酸-p-环糊精(6-Suc-CD)。并将6-Gly-CD和6-Suc-CD继续与反式-R,R-1,2-环己二胺键接,形成环糊精-环己二胺键接物,所得产物利用质谱与核磁共振氢谱进行结构表征。 4、制备单-6-去氧-反式-R,R-1,2-环己二胺-p-环糊精与碘亚铂酸钾的配合物(6-dach-CD-PtI2),配合物用质谱和核磁共振氢谱进行结构表征。
[Abstract]:Platinum antitumor drugs have become one of the main drugs in the treatment of malignant tumors due to their unique mechanism of action. However, the lack of targeting, side effects, drug resistance and other problems have become obstacles to its expanded clinical application. Supramolecular chemical drug delivery system has attracted more and more attention in recent years because of its good safety and low toxicity. Inclusion complexes or bond junctions formed by supramolecular macrocyclic compounds with platinum antitumor complexes enhance the water solubility, stability and safety of platinum drugs. And because of its potential tumor tissue and organ targeting, it has become a hot research direction in the development of new platinum antitumor drugs. Cyclodextrins, as second generation supramolecular macrocyclic compounds, are widely used in the construction and synthesis of drugs. The new drug delivery system, which combines platinum with cyclodextrin, can overcome the drug resistance problem of classical platinum antitumor drugs in the mechanism of anti-tumor action and cell uptake mechanism, which is different from the conventional platinum anti-tumor drugs. The use of macrocyclic compounds to target drug transport can also reduce the side effects of traditional platinum antitumor drugs. In this paper, a series of cyclodextrin-cyclohexane diamine bond conjugates were constructed to be the carriers of new platinum antitumor drugs, so as to overcome many problems in the treatment of platinum drugs. At the same time, the preparation of 6-OTs-CD was pilot-scale production, and tartaric acid was used for the resolution of mixed 1 ~ (2 +) cyclohexanediamine. The main contents of this thesis are as follows: 1. Single 6-deoxy-p-toluenesulfonyl-p-cyclodextrin (6-OTs-CD) was prepared and amplified to pilot production. The product was characterized by nuclear magnetic resonance spectroscopy (NMR). 2. The mixed 1h2cyclohexanediamine was chemically separated by L / D- tartaric acid, and then the trans R- (R)-(-)-(2) -cyclohexanediamine, the "trans-S"-(S)-(1)-(2)-cyclohexanediamine and the cis-12-cyclohexanediamine were separated respectively. The configuration of the product was determined by melting point determination and specific optical rotation, and the 6-OTs-CD was further replaced by derivative. Mono-6-deoxy-trans-R- (1) -cyclohexanediamine (6-dach-CD), mono-6-deoxy-glycine-p-cyclodextrin (6-Gly-CD) and mono-6-deoxy-succinic acid-pcyclodextrin (6-Suc-CD) were prepared. 6-Gly-CD and 6-Suc-CD were continued to be bonded with trans-R- (R-1) -2-cyclohexanediamine to form cyclodextrin-cyclohexanediamine bond. The products were characterized by mass spectrometry and nuclear magnetic resonance (NMR). 4 the complexes of monohexanediamine and potassium iodiplatinate (6-dach-CD-PtI2) were prepared. The complexes were characterized by mass spectrometry and nuclear magnetic resonance (NMR).
【学位授予单位】：昆明理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R91

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