本文選題：電子順磁共振 + 側(cè)鏈取代　； 參考：《天津醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:近年來,全取代三苯甲基(trityl)自由基在磁共振領(lǐng)域備受關(guān)注,相較于氮氧自由基此類自由基具有以下優(yōu)點(diǎn):較高的生物穩(wěn)定性、狹窄的電子順磁共振(EPR)單線信號、較長的弛豫時(shí)間(無氧條件下10μs at 25℃)和較高的檢測敏感性等。目前,trityl自由基在電子順磁共振(EPR)波譜和成像領(lǐng)域具有廣泛的應(yīng)用,包括細(xì)胞內(nèi)和細(xì)胞外氧氣水平、O2·-、p H、氧化還原態(tài)等參數(shù)的檢測;此外,它們在動態(tài)核極化(DNP)增強(qiáng)的核磁波譜與成像和自旋標(biāo)記等領(lǐng)域的應(yīng)用也受到密切關(guān)注。Trityl自由基OX063具有良好的水溶性和生物相容性,是最受關(guān)注的探針之一,但是它的合成是一個(gè)巨大的挑戰(zhàn),限制了其廣泛的應(yīng)用。因此,具有成熟合成路線的CT-03自由基成為研究者們的首要選擇。但是CT-03作為自旋探針存在一些不足,例如對芳環(huán)上羧基的修飾缺乏選擇性,且修飾后會降低其水溶性和弛豫時(shí)間,從而改變它的氧化還原性質(zhì)和EPR譜線,并且可能帶來超精細(xì)裂分等問題。針對上述問題,本文開展了側(cè)鏈單(或雙)取代trityl自由基的工作,設(shè)計(jì)合成了多個(gè)側(cè)鏈可修飾的trityl自由基,并對其性質(zhì)進(jìn)行研究,以期得到具有狹窄EPR信號的高水溶性、可選擇性修飾的trityl自由基。方法:以1,2,4,5-四(叔丁基硫代)苯、丙酮和丙酮酸乙酯為起始原料,經(jīng)縮酮化反應(yīng)、還原反應(yīng)、羥基保護(hù)3步反應(yīng),合成了側(cè)鏈單(或雙)羥基取代的trityl單體,并考察加料順序、溶劑、溫度以及反應(yīng)物的當(dāng)量比對反應(yīng)的影響。通過“1+2”的策略即側(cè)鏈單(或雙)取代的單體與芳基酮反應(yīng)制備三苯甲醇中間體,并對側(cè)鏈單取代中間體利用手性試劑進(jìn)行了構(gòu)型拆分,探討構(gòu)型對性質(zhì)的影響。然后經(jīng)n-Bu Li拔氫與碳酸二甲酯反應(yīng)、水解、脫保護(hù)基、引入官能團(tuán)和變自由基等步驟得到側(cè)鏈具有不同官能團(tuán)取代的trityl自由基,并用EPR方法對其進(jìn)行表征。結(jié)果:實(shí)現(xiàn)了側(cè)鏈單(或雙)取代trityl自由基的高效合成。(1)得到了5個(gè)含有不同官能基團(tuán)的側(cè)鏈單取代trityl自由基的前體,并用NMR、HPLC等方法確認(rèn)其結(jié)構(gòu)和純度;選擇其中2個(gè)前體轉(zhuǎn)變成自由基,并研究側(cè)鏈修飾對trityl自由基EPR性質(zhì)的影響;用(-)-氯代樟腦酸作為拆分試劑,實(shí)現(xiàn)了外消旋化合物7的分離,得到4個(gè)組分,采用NMR和圓二色譜(CD)的方法對其結(jié)構(gòu)進(jìn)行表征,并用EPR方法研究了相應(yīng)的trityl自由基。(2)合成得到了反式和順式側(cè)鏈雙取代三苯甲醇中間體,并得到了順式側(cè)鏈雙羥基取代單體的單晶結(jié)構(gòu)。結(jié)論:(1)本論文實(shí)驗(yàn)方案中所使用的合成路徑,具有方法簡單、操作簡便、重現(xiàn)性好、條件溫和等優(yōu)點(diǎn)。(2)實(shí)現(xiàn)了結(jié)構(gòu)新穎的側(cè)鏈單取代trityl自由基的首次合成,證實(shí)trityl自由基的側(cè)鏈單取代基本不影響其EPR性質(zhì),并解決了trityl自由基的衍生化無選擇性的問題。(3)手性拆分得到了4個(gè)組分,NMR和EPR研究均表明trityl的螺旋槳構(gòu)型對其性質(zhì)有影響。(4)該研究對于設(shè)計(jì)合成新型trityl自由基母核、trityl自由基的功能化、研究三苯甲基衍生物的螺旋槳構(gòu)型及拓展trityl自由基的生物醫(yī)學(xué)應(yīng)用具有重要的意義。
[Abstract]:Objective: in recent years, the total substitution of three benzyl (trityl) free radicals has attracted much attention in the field of magnetic resonance. Compared with the free radical of nitrogen and oxygen free radicals, the free radical has the following advantages: high biological stability, narrow electronic paramagnetic resonance (EPR) single line signal, longer relaxation time (10 s at 25 C under oxygen free conditions) and higher detection sensitivity. At present, trityl free radicals are widely used in the field of electron paramagnetic resonance (EPR) spectroscopy and imaging, including intracellular and extracellular oxygen levels, O2 -, P H, redox states and other parameters. In addition, their applications in the field of dynamic nuclear polarization (DNP) enhanced nuclear magnetic spectroscopy, imaging and spin labeling have also been closely concerned with.Tri Tyl free radical OX063 has good solubility in water and biocompatibility, it is one of the most concerned probes, but its synthesis is a huge challenge, limiting its wide application. Therefore, the CT-03 free radical with mature synthetic route has become the primary choice for researchers. But there are some shortcomings of CT-03 as a spin probe, for example. The modification of the carboxyl group on the aromatic ring is lack of selectivity, and the modification will reduce its water solubility and relaxation time, which will change its redox properties and EPR lines, and may bring about hyperfine splitting and other problems. In this paper, the work of side chain single (or double) substitution of trityl radical is carried out, and multiple side chain repairable is designed and synthesized. The trityl free radical is decorated and its properties are studied in order to obtain the highly water-soluble and selective modified trityl radical with a narrow EPR signal. Method: with 1,2,4,5- four (tert butyl thiosulfate) benzene, acetone and ethyl pyruvate as starting materials, the side chain single (or double) is synthesized by the ketone reaction, reduction reaction and hydroxyl protection of the 3 step reaction. The hydroxyl substituted trityl monomers were used to investigate the effects of the addition order, the solvent, temperature and the equivalent ratio of the reactants. The three benzyl alcohol intermediates were prepared by the reaction of "1+2" strategy, the monomers of side chain single (or double) substituted with aryl ketones, and the configuration of the side chain mono substituted intermediates by the chiral reagent. The effect of the properties. Then by n-Bu Li extraction with two methyl carbonate, hydrolysis, deprotection, the introduction of functional groups and variable free radicals, the side chain with different functional groups to replace the trityl radical, and EPR method to characterize it. Results: the realization of side chain single (or double) substitution of trityl free radical high efficient synthesis. (1) obtained 5 A side chain with different functional groups was substituted for the precursor of single substituent trityl radical, and its structure and purity were confirmed by NMR, HPLC. 2 of the precursors were transformed into free radicals, and the effect of side chain modification on the EPR properties of trityl radicals was studied. The separation of racemic compound 7 was realized by using (-) - chlorocamphor acid as a resolution reagent. To 4 components, the structure was characterized by NMR and circular two chromatography (CD), and the corresponding trityl radical was studied by EPR method. (2) the trans cis side chain double substituted three benzyl alcohol intermediate was synthesized and the single crystal structure of the cis side chain dihydroxyl substituted monomer was obtained. Conclusion: (1) the experimental scheme used in this paper is used. The synthesis path has the advantages of simple method, simple operation, good reproducibility and mild conditions. (2) the first synthesis of the novel side chain single substituent trityl free radical is realized. It is proved that the single substitution of the side chain of the trityl radical does not affect its EPR properties, and solves the problem of the non selectivity of the derivative of the trityl radical. (3) chiral separation 4 components are obtained. The NMR and EPR studies show that the propeller configuration of trityl has an effect on its properties. (4) the study is of great significance for the design and synthesis of a new type of trityl free radical, the functionalization of trityl radical, the study of the propeller configuration of three benzyl derivatives and the development of the biomedical applications of trityl radical.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：O621.146

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