反式—左旋-1,2-環(huán)己二胺—環(huán)糊精鍵接物的設(shè)計(jì)、合成與結(jié)構(gòu)表征
發(fā)布時(shí)間：2018-08-31 16:55
【摘要】：鉑類(lèi)抗腫瘤藥物因其獨(dú)特的作用機(jī)制、廣泛的抗癌譜成為治療惡性腫瘤的主要藥物之一,但無(wú)靶向性、毒副作用、耐藥性等問(wèn)題成為了限制其擴(kuò)大臨床應(yīng)用的障礙。 超分子化學(xué)給藥體系以其所具有的良好的安全性和低毒性近年來(lái)逐漸受到人們的關(guān)注。超分子大環(huán)化合物與鉑類(lèi)抗腫瘤配合物形成的包合物或鍵接物增強(qiáng)了鉑類(lèi)藥物的水溶性、穩(wěn)定性和安全性,并且因?yàn)榫哂袧撛诘哪[瘤組織和器官靶向性成為了新型鉑類(lèi)抗腫瘤藥物開(kāi)發(fā)的一個(gè)熱門(mén)的研究方向。 環(huán)糊精作為第二代超分子大環(huán)化合物,目前被廣泛的用于藥物的構(gòu)建與合成中。將鉑類(lèi)藥物與環(huán)糊精結(jié)合形成的新型給藥體系,其在抗腫瘤作用機(jī)制和細(xì)胞攝取機(jī)制上,不同于常規(guī)的鉑類(lèi)抗腫瘤藥物,能克服經(jīng)典鉑類(lèi)抗腫瘤藥物具有的耐藥性問(wèn)題,利用大環(huán)化合物所具備的靶向藥物轉(zhuǎn)運(yùn)能力,也能夠降低傳統(tǒng)鉑類(lèi)抗腫瘤藥物的副作用。 本文主要研究構(gòu)建一系列環(huán)糊精-環(huán)己二胺鍵接物,以期作為新型鉑類(lèi)抗腫瘤藥物的載體,從而克服目前鉑類(lèi)藥物在治療中所面對(duì)的諸多問(wèn)題。同時(shí),也將6-OTs-CD的制備進(jìn)行了中試生產(chǎn),并研究了利用酒石酸對(duì)混合的1,2-環(huán)己二胺進(jìn)行拆分。 本論文研究具體內(nèi)容如下： 1、制備單-6-去氧-對(duì)甲苯磺�；�-p-環(huán)糊精(6-OTs-CD),并將其放大至中試生產(chǎn),所得產(chǎn)物通過(guò)核磁共振氫譜進(jìn)行了結(jié)構(gòu)表征。 2、利用L/D-酒石酸對(duì)混合1,2-環(huán)己二胺進(jìn)行化學(xué)手性拆分,分別分離出反式-R,R-1,2-環(huán)己二胺,反式-S,S-1,2-環(huán)己二胺和順式-1,2-環(huán)己二胺。所得產(chǎn)物通過(guò)熔點(diǎn)測(cè)定,比旋光度測(cè)定確定其構(gòu)型。 3、將6-OTs-CD進(jìn)一步取代衍生,制備單-6-去氧-反式-R,R-1,2-環(huán)己二胺-p-環(huán)糊精(6-dach-CD)、單-6-去氧-甘氨酸-p-環(huán)糊精(6-Gly-CD)和單-6-去氧-琥珀酸-p-環(huán)糊精(6-Suc-CD)。并將6-Gly-CD和6-Suc-CD繼續(xù)與反式-R,R-1,2-環(huán)己二胺鍵接,形成環(huán)糊精-環(huán)己二胺鍵接物,所得產(chǎn)物利用質(zhì)譜與核磁共振氫譜進(jìn)行結(jié)構(gòu)表征。 4、制備單-6-去氧-反式-R,R-1,2-環(huán)己二胺-p-環(huán)糊精與碘亞鉑酸鉀的配合物(6-dach-CD-PtI2),配合物用質(zhì)譜和核磁共振氫譜進(jìn)行結(jié)構(gòu)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).
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R914.5;R91
本文編號(hào)：2215590
[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).
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R914.5;R91
【參考文獻(xiàn)】
相關(guān)期刊論文 前4條
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，本文編號(hào)：2215590
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