基于2-硝基咪唑的低氧激活前药

发布时间：2018-03-22 23:15

  本文选题：碳酸酯前药　切入点：2-硝基咪唑　出处：《华东师范大学》2017年硕士论文　论文类型：学位论文

【摘要】：近年来,肿瘤的发病率和致死率正在逐年攀升,化疗药物是肿瘤治疗的重要手段。传统的抗肿瘤药物(如:紫杉醇、喜树碱)具有毒副作用大,溶解性差,易产生多药耐药性等缺陷,因此开发具有选择性的新型抗肿瘤药物是研究发展的重要方向,目前越来越多的研究人员把目光聚集到对其前药的开发上。紫杉醇2'位羟基和喜树碱20位羟基的碳酸酯前药的开发近年来颇受关注。但是由于这类碳酸酯前药在人体内较差的药物释放率,限制了它们的临床应用,所以开发新型的紫杉醇、喜树碱类的碳酸酯前药尤为重要。低氧作为肿瘤的一个很重要的特征,调控着肿瘤的生长、基因的表达等重要的信息。所以以低氧为靶点开发低氧激活前药是近年来研究的热门领域。2-硝基咪唑可以对肿瘤的低氧环境做出应答,它所含有的硝基可以被低氧组织中高表达的还原性酶还原,进而释放出活性药物,所以2-硝基咪唑广泛的应用于低氧激活前药的开发。本论文首先设计合成了以对羟基苄醇为连接体的紫杉醇碳酸酯前药,但是由于这类前药过于不稳定所以中止了对它们的研究,随后设计了以2-硝基咪唑为靶头,在2-硝基咪唑的1位N上进行衍生化得到2-硝基咪唑烷醇,通过碳酸酯键与传统的抗肿瘤药物(紫杉醇、SN-38)相连接而成的四个低氧激活前药。在低氧条件下,它们被还原成为2-氨基咪唑中间体,它可以促进碳酸酯键的水解,从而释放活性药物,增加了低氧的选择性。在化学还原实验和硝基还原酶实验中更进一步验证了前药的释药机制。PBS的稳定性实验、人血浆和小鼠血浆稳定性实验证明了这四种前药在人血浆和PBS中具有一定的的稳定性,硝基还原酶条件下前药能够迅速还原释放出活性药物,其中化合物13(2C-PTX)在一小时内它释放了 85%的紫杉醇,说明硝基咪唑的还原能够促进碳酸酯键的裂解释药。细胞毒实验来看,四种前药都具有一定的低氧选择性,其中在H460细胞株上化合物7(3C-SN38)表现出了 2倍的低氧选择性,在HT29细胞株上化合物13(2C-PTX)表现出了 3倍的低氧选择性。本论文设计的这种新型的硝基咪唑类低氧激活前药具有新的药物释放机制,对低氧肿瘤细胞具有一定的选择性,为以后低氧激活前药的发展具有一定的借鉴意义。
[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.

【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914
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本文编号：1650826