博来霉素二糖、DP-b99及其衍生物的合成

发布时间：2018-02-02 10:06

  本文关键词： 博来霉素二糖 DP-b99 衍生物 合成　出处：《中国海洋大学》2014年硕士论文　论文类型：学位论文

【摘要】：博来霉素(Bleomycin)是一种由轮枝链霉菌(Streptomyces verticillus)产生的糖肽类抗生素,主要用于治疗霍奇金氏淋巴瘤、鳞状细胞癌、宫颈癌和睾丸癌等,为一线治疗药物。博来霉素的基本骨架是由二糖和若干氨基酸组成的寡肽连接而成,主要通过与DNA结合发挥抗肿瘤作用。最新研究表明,博来霉素的二糖部分对于肿瘤细胞具有特异性的识别作用,而对于正常的细胞则无结合效力。这表明二糖部分在博来霉素的抗肿瘤过程中发挥重要的靶向肿瘤细胞的作用,但具体作用机制尚不清楚。为了进一步研究博来霉素二糖与肿瘤细胞的结合位点及靶向作用机制,本论文通过博来霉素二糖的合成方法和策略的研究,设计合成博来霉素二糖及其相关衍生物,为该类化合物的生物学研究提供物质基础。DP-b99是一种膜-活化的锌、钙离子螯合剂,经膜活化后可与脑部神经细胞中过量的锌离子、钙离子螯合,减轻脑缺血再灌注后的级联反应引起的细胞损伤,DP-b99是一种用于急性缺血性中风预防和治疗的药物,但是由于疗效不足导致三期临床研究失败,因此进一步增强DP-b99的药效是该类化合物未来的研究重点。硫化氢是一种重要的内源性的气体信号分子,具有较好的扩张血管及神经保护作用,本论文通过在DP-b99分子中引入可以产生硫化氢的基团设计合成系列衍生物,期望通过硫化氢与DP-b99协同作用提高该类化合物的抗中风与神经保护作用。1、博来霉素二糖及其衍生物的合成博来霉素二糖是由3-O-氨甲酰基-D-甘露糖和L-古洛糖通过α1,2-糖苷键连接而成。在博来霉素二糖的合成中,本论文分别制备不同类型的甘露糖供体和2-OH裸露的古洛糖受体,然后通过糖苷化反应进行偶联获得二糖。在甘露糖供体的合成中,以甘露糖甲基苷为起始原料,经八步反应,分别以25.3%和33.5%的总收率得到了甘露糖磷酸酯供体2,4,6-Tri-O-acetyl-3-O-carbamoyl-α-D-Mannopyranosyl Diphenyl Phosphate (9-1)和甘露糖三氯亚胺酯供体2,4,6-Tri-O-acetyl-3-O-carbamoyl-α-D-Mannopyranosyl trichloroacetimidate (9-2)。古洛糖受体的合成中,首先以古洛糖醛酸-γ-内酯作为起始原料,经七步反应,以29.6%的总收率得到了新型博来霉素二糖古洛糖受体p-Methylphenyl4,6-O-Benzylidene-3-O-acetyl-1-thio-β-L-gulopyranoside (G-7)。随后又以半乳糖为起始原料,利用SN2亲核取代反应,使半乳糖3-OH构型翻转,得到古洛糖构型产物,共经八步反应以47%的总收率制备了古洛糖受体G-7(X-8),该制备方法具有操作简便、易分离纯化、收率高等优点、适合大量制备。在糖苷化反应中,将甘露糖供体9-2和古洛糖受体G-7偶联,以77%的收率得到全保护的博来霉素二糖硫苷F-1。随后在博来霉素二糖的还原端引入末端含不同功能基团(氯、叠氮基)的连接臂得到系列博来霉素二糖衍生物,为下步将博来霉素二糖与抗肿瘤药物偶联及其相关的生物学研究提供了物质基础。2、DP-b99及其衍生物的合成以膜活化螯合剂DP-b99为先导化合物,通过对其苯环部分及侧链部分的结构修饰,制备系列DP-b99的衍生物。苯环上具有不同取代基的酸酐中间体的合成：以邻硝基酚为起始原料,分别经五步和六步反应,以1 9.8%和15.3%的总收率得到DP-b99酸酐中间体BAPTA-Anhydride (A-5)和硝基取代酸酐中间体5,5'-Dinitro-B APTA-Anhydride(B-3)；以5-甲基-2-硝基苯酚为起始原料,经五步反应,以27.6%的总收率得到甲基取代酸酐中间体5,5'-dimethyl BAPTA-Anhydride (C-5)。侧链部分的合成：以溴代正辛烷为原料,以60%的收率合成了DP-b99的侧链ethylene glycol monooctyl ether (CL-a);以硫辛酸为原料,以86.8%的收率合成了含硫侧链ethylene glycol monoprotogen ether (CL-c)。DP-b99及其含硫衍生物的合成：在分别得到了上述不同类型的酸酐中间体及侧链后,经酯化反应,顺利得到终产物DP-b99及含硫衍生物ethyl thioglycolate thioester of BAPTA (A-b)。本论文通过对博来霉素二糖及其衍生物的合成研究,建立了一种新型高效的博来霉素二糖的合成策略,同时为博来霉素二糖进一步的生物学研究奠定了基础。通过对神经保护剂DP-b99及其系列衍生物的设计合成,为进一步研究DP-b99的构效关系与作用机制提供了物质基础。
[Abstract]:Bleomycin (Bleomycin) is a kind of from Streptoverticillium (Streptomyces verticillus) of glycopeptide antibiotics produced, mainly used for the treatment of Hodge lymphoma and squamous cell carcinoma, cervical cancer and testicular cancer, as first-line therapy. Bleomycin is the basic skeleton of oligo peptide composed of two amino acids and some sugar the connection is made mainly by DNA combined with the anti-tumor effect. The latest research shows that the recognition effect of bleomycin for two sugar tumor cells with specificity, whereas the normal cells have no binding effect. This shows that the two sugar moieties in bleomycin antitumor plays an important target to tumor cells, but the specific mechanism is still not clear. In order to further study the combination of bleomycin two sugar and tumor cell and site targeting mechanism, this paper through the synthesis method of lincomycin Bo two sugar Research and strategy, design and synthesis of bleomycin two sugar and its derivatives, to provide the material basis of.DP-b99 is a membrane - activated zinc for biological research of the compounds, calcium chelating agent, the membrane can be activated with an excess of zinc ions in nerve cells in the brain, calcium chelation, cell damage reduce the damage after cerebral ischemia reperfusion in the cascade reaction, DP-b99 is a kind of drug for the prevention and treatment of acute ischemic stroke, but due to lack of efficacy of phase three clinical studies failed, so to further enhance the effectiveness of DP-b99 is the focus of research on the compounds in the future. The gas hydrogen sulfide is an important signal molecule in endogenous with the expansion of blood vessels and nerves, good protective effect, this paper by introducing a series of synthetic group design derivatives can produce hydrogen sulfide in DP-b99 molecule, through hydrogen sulfide and DP-b9 The compound effect of anti stroke and neuroprotective.1 9 synergistic effect, Bo synthesis bleomycin two sugar and its derivatives to kanamycin two sugar by 3-O- carbamoyl -D- mannose and L- gulose by alpha 1,2- glycosidic. In the synthesis of bleomycin sugar in two mannose, were prepared with different donor and 2-OH exposed gulose receptor in this paper, and then through the glycosylation reaction coupling two sugar. In the synthesis of mannose donor, with mannose methyl glycosides as the starting material, through eight steps, respectively to 25.3% and 33.5% of the total yield by mannose phosphate a -D-Mannopyranosyl Diphenyl Phosphate donor 2,4,6-Tri-O-acetyl-3-O-carbamoyl- (9-1) and mannose three chloro imine ester donor 2,4,6-Tri-O-acetyl-3-O-carbamoyl- alpha -D-Mannopyranosyl trichloroacetimidate (9-2). Gulose receptor synthesis in ,棣栧厛浠ュ彜娲涚硸閱涢吀-纬-鍐呴叝浣滀负璧峰�嬪師鏂�,缁忎竷姝ュ弽搴，

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