生物素介导的基于鬼臼毒素的配体靶向药物传递系统的设计、合成和生物评价及氮杂环化合物库的构建

发布时间：2018-01-04 11:22

本文关键词：生物素介导的基于鬼臼毒素的配体靶向药物传递系统的设计、合成和生物评价及氮杂环化合物库的构建　出处：《浙江大学》2017年硕士论文　论文类型：学位论文

【摘要】：恶性肿瘤是严重威胁人类生命健康的常见病和多发病。传统的治疗方法存在着选择性差、毒副作用大及易产生耐药等缺点。配体靶向药物传递系统则是以肿瘤细胞表面某些过度表达的受体为靶点,利用受体与配体的特异性反应,使配体与受体结合,具有导向作用的配体将药物靶向传送到肿瘤位点,从而实现主动靶向给药。近年来,配体靶向药物传递系统已经成为开发抗癌和抗肿瘤药物的有效手段。由于小分子有机化合物配体的相对较低的分子量、可以迅速扩散出血管,进而快速渗透到组织深处的特点,以小分子有机化合物为配体的靶向药物传递系统引起了药学工作者更广泛的关注。而鬼臼毒素是一种具有天然活性的木质素类化合物,近年来许多研究表明鬼臼毒素是一类非常重要的具有抗肿瘤作用的先导化合物,其衍生物的抗肿瘤活性也一直备受关注。本论文对文献中报道的及有临床应用的配体靶向药物传递系统进行了综述,并对鬼臼毒素的抗肿瘤作用机制及其构效关系进行了讨论,同时综述了小分子-药物共轭物的设计原则。在此基础上,我们以生物素为配体,可自裂解的二硫键为连接桥,4’-去甲基表鬼臼毒素为活性药物设计合成了两个小分子-药物共轭物。所有的目标化合物均经过1H NMR、13C NMR、HPLC-HRMS和熔点表征。在体外肿瘤细胞筛选中,所设计的化合物对生物素受体过表达的人早幼粒急性白血病细胞株HL-60 (BR+)和人宫颈癌细胞株Hela (BR+)有较好的增殖抑制活性,但是略低于阳性药物依托泊苷。所合成化合物的后续靶向性和作用机制研究仍在继续。化合物库的高通量筛选依然是新药发现的主要途径之一,含氮杂环在已上市的药物中占有很大的比例,因此构建数量巨大的含氮杂环化合物库对于发现先导化合物具有极其重要的意义。论文的第三部分利用新的化学方法构建了三类共计50个含氮杂环化合物。首先,我们以烯烃叠氮化合物和2-羟基-1,4-萘醌为原料,在乙酸锰催化条件下,开发了一种新型的、简便的、经济的方法来实现高产率地制备功能化的苯并[7]吲哚-4,9-二酮类化合物。其次,我们以烯烃叠氮化合物和4-羟基香豆素为原料,经过烯烃叠氮的热转化、分子内亲核进攻和4-exo-trig环合,构建出结构新颖的螺苯并呋喃环内酰胺类化合物。最后,我们以α-硝基环氧化合物、单氰胺和Na2S·9H2O为起始原料开发了一种简便的、三组分“一锅法”制备多取代2-氨基噻唑化合物的方法。这三个含氮杂环化合库的所有目标化合物的结构均经过1HNMR、13CNMR、HPLC-HRMS和熔点表征,它们的生物评价也在进行中。
[Abstract]:Malignant tumors are common diseases and frequent diseases that threaten human life and health seriously. The traditional treatment methods have poor selectivity. The ligand-targeted drug delivery system is targeted at some over-expressed receptors on the surface of tumor cells and binds the ligand to the receptor by using the specific reaction between the receptor and the ligand. In recent years, ligands that have the ability to direct drug delivery target to tumor sites, so as to achieve active targeting drug delivery in recent years. Ligand-targeted drug delivery system has become an effective means to develop anticancer and anti-tumor drugs. Because of the relatively low molecular weight of small molecular organic compounds ligands can rapidly spread out of blood vessels. And then quickly penetrate deep into the tissue. Targeting drug delivery systems with small molecular organic compounds as ligands have attracted more and more attention from pharmacists. Podophyllotoxin is a lignin compound with natural activity. In recent years, many studies have shown that podophyllotoxin is a very important leading compound with anti-tumor effect. The antitumor activity of its derivatives has been attracting much attention. In this paper, the ligands targeted drug delivery systems reported in the literature and have clinical applications are reviewed. The anti-tumor mechanism and structure-activity relationship of podophyllotoxin were discussed, and the design principles of small molecular-drug conjugate were reviewed. On this basis, biotin was used as ligand. Two small molecular-drug conjugates were designed and synthesized by self-cleavage of disulfide bonds as the active drugs. All the target compounds passed through 1H NMR. 13C-NMR-HPLC-HRMS and melting point characterization. In vitro screening of tumor cells. The designed compounds have good proliferative inhibitory activity on human promyelocytic acute leukemia cell line (HL-60 / Br) and human cervical cancer cell line (Hela / Br), which are overexpression of biotin receptor. However, the further studies on the targeting and action mechanism of the synthesized compounds are still continuing, and the high throughput screening of the compound library is still one of the main approaches to the discovery of new drugs. Nitrogen-containing heterocyclic compounds account for a large proportion of the drugs on the market. Therefore, the construction of a large number of nitrogen-containing heterocyclic compounds library is of great significance for the discovery of lead compounds. In the third part of the thesis, we constructed three kinds of heterocyclic compounds with 50 nitrogen heterocyclic compounds by a new chemical method. First. In this paper, a new, simple and economical method for the preparation of functional benzo in high yield was developed under the condition of manganese acetate catalyzed by alkenes azide compounds and 2-hydroxy-1n 4-naphthoquinone. [7] indole -4N _ 9-diketone compounds. Secondly, we used azido alkenes and 4-hydroxycoumarin as raw materials to undergo the thermal conversion of azido alkenes. The novel spirobenzofuran cyclolactam compounds were synthesized by intramolecular nucleophilic attack and 4-exo-trig cyclization. Finally, 伪 -nitro-epoxides were synthesized. Monocyanamide and Na2S 路9H2O were used as starting materials to develop a simple method. The method of preparing polysubstituted 2-aminothiazole compounds by "one pot method" with three components. All the target compounds containing heterocyclic compounds containing nitrogen have all the structures passed through 1HNMR-13CNMR. HPLC-HRMS and melting point characterization, their biological evaluation is also in progress.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91;R914.5

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