本文關鍵詞： 博來霉素二糖 DP-b99 衍生物 合成　出處：《中國海洋大學》2014年碩士論文　論文類型：學位論文

【摘要】：博來霉素(Bleomycin)是一種由輪枝鏈霉菌(Streptomyces verticillus)產(chǎn)生的糖肽類抗生素,主要用于治療霍奇金氏淋巴瘤、鱗狀細胞癌、宮頸癌和睪丸癌等,為一線治療藥物。博來霉素的基本骨架是由二糖和若干氨基酸組成的寡肽連接而成,主要通過與DNA結(jié)合發(fā)揮抗腫瘤作用。最新研究表明,博來霉素的二糖部分對于腫瘤細胞具有特異性的識別作用,而對于正常的細胞則無結(jié)合效力。這表明二糖部分在博來霉素的抗腫瘤過程中發(fā)揮重要的靶向腫瘤細胞的作用,但具體作用機制尚不清楚。為了進一步研究博來霉素二糖與腫瘤細胞的結(jié)合位點及靶向作用機制,本論文通過博來霉素二糖的合成方法和策略的研究,設計合成博來霉素二糖及其相關衍生物,為該類化合物的生物學研究提供物質(zhì)基礎。DP-b99是一種膜-活化的鋅、鈣離子螯合劑,經(jīng)膜活化后可與腦部神經(jīng)細胞中過量的鋅離子、鈣離子螯合,減輕腦缺血再灌注后的級聯(lián)反應引起的細胞損傷,DP-b99是一種用于急性缺血性中風預防和治療的藥物,但是由于療效不足導致三期臨床研究失敗,因此進一步增強DP-b99的藥效是該類化合物未來的研究重點。硫化氫是一種重要的內(nèi)源性的氣體信號分子,具有較好的擴張血管及神經(jīng)保護作用,本論文通過在DP-b99分子中引入可以產(chǎn)生硫化氫的基團設計合成系列衍生物,期望通過硫化氫與DP-b99協(xié)同作用提高該類化合物的抗中風與神經(jīng)保護作用。1、博來霉素二糖及其衍生物的合成博來霉素二糖是由3-O-氨甲酰基-D-甘露糖和L-古洛糖通過α1,2-糖苷鍵連接而成。在博來霉素二糖的合成中,本論文分別制備不同類型的甘露糖供體和2-OH裸露的古洛糖受體,然后通過糖苷化反應進行偶聯(lián)獲得二糖。在甘露糖供體的合成中,以甘露糖甲基苷為起始原料,經(jīng)八步反應,分別以25.3%和33.5%的總收率得到了甘露糖磷酸酯供體2,4,6-Tri-O-acetyl-3-O-carbamoyl-α-D-Mannopyranosyl Diphenyl Phosphate (9-1)和甘露糖三氯亞胺酯供體2,4,6-Tri-O-acetyl-3-O-carbamoyl-α-D-Mannopyranosyl trichloroacetimidate (9-2)。古洛糖受體的合成中,首先以古洛糖醛酸-γ-內(nèi)酯作為起始原料,經(jīng)七步反應,以29.6%的總收率得到了新型博來霉素二糖古洛糖受體p-Methylphenyl4,6-O-Benzylidene-3-O-acetyl-1-thio-β-L-gulopyranoside (G-7)。隨后又以半乳糖為起始原料,利用SN2親核取代反應,使半乳糖3-OH構(gòu)型翻轉(zhuǎn),得到古洛糖構(gòu)型產(chǎn)物,共經(jīng)八步反應以47%的總收率制備了古洛糖受體G-7(X-8),該制備方法具有操作簡便、易分離純化、收率高等優(yōu)點、適合大量制備。在糖苷化反應中,將甘露糖供體9-2和古洛糖受體G-7偶聯(lián),以77%的收率得到全保護的博來霉素二糖硫苷F-1。隨后在博來霉素二糖的還原端引入末端含不同功能基團(氯、疊氮基)的連接臂得到系列博來霉素二糖衍生物,為下步將博來霉素二糖與抗腫瘤藥物偶聯(lián)及其相關的生物學研究提供了物質(zhì)基礎。2、DP-b99及其衍生物的合成以膜活化螯合劑DP-b99為先導化合物,通過對其苯環(huán)部分及側(cè)鏈部分的結(jié)構(gòu)修飾,制備系列DP-b99的衍生物。苯環(huán)上具有不同取代基的酸酐中間體的合成：以鄰硝基酚為起始原料,分別經(jīng)五步和六步反應,以1 9.8%和15.3%的總收率得到DP-b99酸酐中間體BAPTA-Anhydride (A-5)和硝基取代酸酐中間體5,5'-Dinitro-B APTA-Anhydride(B-3)；以5-甲基-2-硝基苯酚為起始原料,經(jīng)五步反應,以27.6%的總收率得到甲基取代酸酐中間體5,5'-dimethyl BAPTA-Anhydride (C-5)。側(cè)鏈部分的合成：以溴代正辛烷為原料,以60%的收率合成了DP-b99的側(cè)鏈ethylene glycol monooctyl ether (CL-a);以硫辛酸為原料,以86.8%的收率合成了含硫側(cè)鏈ethylene glycol monoprotogen ether (CL-c)。DP-b99及其含硫衍生物的合成：在分別得到了上述不同類型的酸酐中間體及側(cè)鏈后,經(jīng)酯化反應,順利得到終產(chǎn)物DP-b99及含硫衍生物ethyl thioglycolate thioester of BAPTA (A-b)。本論文通過對博來霉素二糖及其衍生物的合成研究,建立了一種新型高效的博來霉素二糖的合成策略,同時為博來霉素二糖進一步的生物學研究奠定了基礎。通過對神經(jīng)保護劑DP-b99及其系列衍生物的設計合成,為進一步研究DP-b99的構(gòu)效關系與作用機制提供了物質(zhì)基礎。
[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 ,棣栧厛浠ュ彜媧涚硸閱涢吀-緯-鍐呴叝浣滀負璧峰鍘熸枡,緇忎竷姝ュ弽搴，

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