本文選題：碳酸酯前藥　切入點：2-硝基咪唑　出處：《華東師范大學》2017年碩士論文　論文類型：學位論文

【摘要】：近年來,腫瘤的發(fā)病率和致死率正在逐年攀升,化療藥物是腫瘤治療的重要手段。傳統(tǒng)的抗腫瘤藥物(如:紫杉醇、喜樹堿)具有毒副作用大,溶解性差,易產生多藥耐藥性等缺陷,因此開發(fā)具有選擇性的新型抗腫瘤藥物是研究發(fā)展的重要方向,目前越來越多的研究人員把目光聚集到對其前藥的開發(fā)上。紫杉醇2'位羥基和喜樹堿20位羥基的碳酸酯前藥的開發(fā)近年來頗受關注。但是由于這類碳酸酯前藥在人體內較差的藥物釋放率,限制了它們的臨床應用,所以開發(fā)新型的紫杉醇、喜樹堿類的碳酸酯前藥尤為重要。低氧作為腫瘤的一個很重要的特征,調控著腫瘤的生長、基因的表達等重要的信息。所以以低氧為靶點開發(fā)低氧激活前藥是近年來研究的熱門領域。2-硝基咪唑可以對腫瘤的低氧環(huán)境做出應答,它所含有的硝基可以被低氧組織中高表達的還原性酶還原,進而釋放出活性藥物,所以2-硝基咪唑廣泛的應用于低氧激活前藥的開發(fā)。本論文首先設計合成了以對羥基芐醇為連接體的紫杉醇碳酸酯前藥,但是由于這類前藥過于不穩(wěn)定所以中止了對它們的研究,隨后設計了以2-硝基咪唑為靶頭,在2-硝基咪唑的1位N上進行衍生化得到2-硝基咪唑烷醇,通過碳酸酯鍵與傳統(tǒng)的抗腫瘤藥物(紫杉醇、SN-38)相連接而成的四個低氧激活前藥。在低氧條件下,它們被還原成為2-氨基咪唑中間體,它可以促進碳酸酯鍵的水解,從而釋放活性藥物,增加了低氧的選擇性。在化學還原實驗和硝基還原酶實驗中更進一步驗證了前藥的釋藥機制。PBS的穩(wěn)定性實驗、人血漿和小鼠血漿穩(wěn)定性實驗證明了這四種前藥在人血漿和PBS中具有一定的的穩(wěn)定性,硝基還原酶條件下前藥能夠迅速還原釋放出活性藥物,其中化合物13(2C-PTX)在一小時內它釋放了 85%的紫杉醇,說明硝基咪唑的還原能夠促進碳酸酯鍵的裂解釋藥。細胞毒實驗來看,四種前藥都具有一定的低氧選擇性,其中在H460細胞株上化合物7(3C-SN38)表現(xiàn)出了 2倍的低氧選擇性,在HT29細胞株上化合物13(2C-PTX)表現(xiàn)出了 3倍的低氧選擇性。本論文設計的這種新型的硝基咪唑類低氧激活前藥具有新的藥物釋放機制,對低氧腫瘤細胞具有一定的選擇性,為以后低氧激活前藥的發(fā)展具有一定的借鑒意義。
[Abstract]:In recent years, the incidence of cancer and mortality rates are rising year by year, chemotherapy is an important means of cancer treatment. Traditional cancer drugs (such as paclitaxel, camptothecin) has high toxicity, poor solubility, easy to produce defects of multi drug resistance, so the development of new anticancer drugs selectively is an important direction of research and development, more and more researchers to focus on the development of the prodrug. The development of carbonate paclitaxel 2'hydroxy camptothecin and 20 hydroxy prodrugs of popular concern in recent years. But because of this kind of drug carbonic ester prodrug is poor in human body. The release rate and limit their clinical application, so the development of a new type of paclitaxel, carbonate camptothecin prodrug is particularly important. Hypoxia as a very important feature of the tumor, regulates tumor growth, gene expression and other important information So to target the development of hypoxic hypoxia activated prodrugs is hypoxia 4-nitroimidazole hot areas of.2- research in recent years for tumor response, reduction of nitro containing enzyme it can be highly expressed in tissue hypoxia reduction, and then release the active drug, the development and application of the 2- to 4-nitroimidazole widely in hypoxia activated prodrugs. Firstly, the design and synthesis of hydroxy benzyl alcohol as paclitaxel carbonate before administration of connected, but because this kind of medicine is not so stable before the suspension of the study on them, then to design the 2- nitro imidazole as the target, were derivatized by 2- nitro imidazolidine alcohol at 1 N 2- 4-nitroimidazole, by antineoplastic drugs and traditional carbonate bond (paclitaxel, SN-38) four hypoxia formed connected to the activation of prodrugs. Under hypoxic condition, they are reduced to intermediate 2- amino imidazole The body, it can promote the hydrolysis of the carbonate bond, thereby releasing the active drug, increased oxygen selectivity. In the experiment and the experiment of nitroreductase further verify the.PBS stability test of drug release mechanism of prodrug chemical reduction, human plasma and mouse plasma stability experiment proved that the four kinds of prodrugs have some stability in human plasma and PBS, under the condition of nitroreductase prodrug can quickly release the active drug reduction, compound 13 (2C-PTX) in one hour it released 85% of the paclitaxel, that can promote the reduction of nitro imidazole carbonate bond cleavage release. Cytotoxicity test, four kinds of drugs with a hypoxia selective, which in H460 cell line (3C-SN38) 7 compounds showed selective hypoxia 2 times, in the HT29 cell line on 13 compounds (2C-PTX) showed low oxygen selective 3 times. The design of this new type of nitroimidazole hypoxia activated prodrugs with new drug release mechanism has certain selectivity to hypoxic tumor cells, has a certain reference significance for the development after hypoxia activated prodrugs.

【學位授予單位】：華東師范大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914
，

本文編號：1650826