熒光嘌呤核苷類似物合成及性質(zhì)研究
發(fā)布時(shí)間：2019-06-12 06:34
【摘要】：目的:核苷是核酸(DNA或RNA)的基本組成部分。核苷衍生物廣泛應(yīng)用于藥物研發(fā)、分子探針設(shè)計(jì)、癌癥機(jī)理探討等研究領(lǐng)域,同時(shí)也是臨床常用的抗病毒、抗腫瘤等抗代謝類藥物。核苷分子的堿基和糖基均可以進(jìn)行化學(xué)修飾。堿基的修飾位點(diǎn)眾多,嘌呤核苷的C-8位修飾是合成核苷衍生物重要途徑,也是獲得熒光核苷類似物的有效方法。目前,在2-氨基脫氧腺苷和異鳥苷的8位進(jìn)行修飾的研究較少,本研究擬在2-氨基2'-脫氧腺苷和2'-脫氧異鳥苷的8位進(jìn)行修飾,以期獲取具有抗腫瘤活性以及能用作熒光探針的的新嘌呤核苷。方法:1化合物的制備鹵代嘌呤核苷是堿基修飾的重要中間體。首先,將2-氨基-2'-脫氧腺苷溶于冰醋酸中,加入醋酸鈉,滴加適量溴素,合成8-溴-2-氨基-2'-脫氧腺苷,接著,將其用于Sonogashira反應(yīng),溶于DMF溶液,加入Pd(PPh3)2Cl2/Cu I(1:2),三乙胺(3 eq)及相應(yīng)取代炔烴,微波加熱,合成一系列新的8位炔基取代的2-氨基-2'-脫氧腺苷衍生物;同樣方法,用8-溴腺苷為前體,也合成出一系列8-取代腺苷衍生物。新的8位炔基取代的2-氨基-2'-脫氧腺苷衍生物在醋酸和Na NO2作用下通過生成重氮鹽中間體,嘌呤環(huán)2位氨基轉(zhuǎn)化為羰基,制備出一系列新的8位被炔基取代的脫氧異鳥苷2熒光性質(zhì)研究熒光分光光度計(jì)測量化合物的熒光光譜、熒光量子效率及溶劑極性(二氧六環(huán)、甲醇和水)和溶液p H(1.5-12)值對(duì)化合物熒光光譜的影響。3化合物p Ka值的測定紫外分光光度滴定法測定脫氧異鳥苷衍生物的電離常數(shù)(p Ka);4抗腫瘤活性檢測CCK-8法研究2-氨基-2'-脫氧腺苷、異鳥苷、腺苷衍生物對(duì)MM.1S人多發(fā)性骨髓瘤細(xì)胞生長的抑制作用,Graphpad prism 5統(tǒng)計(jì)實(shí)驗(yàn)結(jié)果,根據(jù)細(xì)胞存活率計(jì)算化合物的GI50。結(jié)果:8-溴-2-氨基-2'-脫氧腺苷的收率為87%;腺苷及2-氨基-2'-脫氧腺苷取代反應(yīng)的產(chǎn)率為76-95%;2'-脫氧異鳥苷衍生物的收率為52-70%;所有化合物通過1HNMR和13C-NMR以及高分辨質(zhì)譜分析,確定結(jié)構(gòu)。苯炔衍生物取代的2-氨基-2'-脫氧腺苷和2'-脫氧異鳥苷有明顯熒光,2'-脫氧異鳥苷衍生物的熒光強(qiáng)度對(duì)環(huán)境敏感,在二氧六環(huán)和水中呈現(xiàn)出不同的激發(fā)波長和發(fā)射波長以及不同的熒光強(qiáng)度,同時(shí),2'-脫氧異鳥苷對(duì)p H敏感,可隨著p H的增加而減弱;與2'-脫氧異鳥苷相比,8位炔基化的異鳥苷衍生物的p Ka值都發(fā)生顯著變化;抗腫瘤活性檢測發(fā)現(xiàn)苯炔衍生物取代的2-氨基-2'-脫氧腺苷和2'-脫氧異鳥苷化合物存在抑制MM.1S增殖的現(xiàn)象;測定化合物2a、2c、4、4a、4b、4c的GI50分別為24.28、21.11、7.87、13.78、10.08、7.10。結(jié)論:在微波輔助下,高收率的合成出一系列新的8位炔基取代的2-氨基-2'-脫氧腺苷和脫氧異鳥苷。8-位被芳香炔基取代的2-氨基-2'-脫氧腺苷、2'-脫氧異鳥苷可產(chǎn)生明顯的熒光。其中,8位芳炔基化的2'-脫氧異鳥苷熒光分子對(duì)微環(huán)境敏感,具有作為熒光探針的前景。部分8-位芳炔基衍生物取代的腺苷、2'-脫氧異鳥苷具有抗腫瘤活性。
[Abstract]:Purpose: The nuclear antigen is a basic component of a nucleic acid (DNA or RNA). The nuclear antigen derivative is widely used in the fields of drug development, molecular probe design, cancer mechanism and the like, and is also an anti-metabolic drug commonly used in clinic, such as anti-virus, anti-tumor and the like. The base and the glycosyl of the nuclear antigen can be chemically modified. The modification site of the base has many modification sites, and the C-8-position modification of the methotrexate core is an important way to synthesize the nuclear antigen derivative, and is also an effective method for obtaining the fluorescent nuclear antigen analog. At present, the 8-bit modification of the 2-amino-2 '-deoxyadeno-and 2'-deoxy-avirences is less, and the study is intended to be modified at the 8-bit of the 2-amino-2 '-deoxyadeno-and 2'-deoxy-iopterin, with a view to obtaining a new methotrexate core with anti-tumor activity and which can be used as a fluorescent probe. Method: The preparation of a compound is an important intermediate of base modification. firstly, dissolving 2-amino-2 '-deoxyadenine in glacial acetic acid, adding sodium acetate, dripping an appropriate amount of bromine, and synthesizing 8-bromo-2-amino-2'-deoxyadenine, then, reacting with Sonogashira, dissolving in DMF solution, adding Pd (PPh3) 2Cl2/ Cu I (1:2), Triethylamine (3 eq) and corresponding substituted acetylenic hydrocarbon, microwave heating, synthesis of a series of new 8-bit alkynyl-substituted 2-amino-2 '-ethanal derivatives; the same method, with 8-bromothymol as a precursor, A series of 8-substituted adenine derivatives are also synthesized. The novel 8-position alkynyl-substituted 2-amino-2 '-deoxyadenine derivative is converted into a diazonium salt intermediate by the generation of a diazonium salt intermediate under the action of acetic acid and Na NO2, The fluorescence spectrum, the fluorescence quantum efficiency and the solvent polarity (dioxane, The influence of the value of methanol and water) and solution p h (1.5 -12) on the fluorescence spectrum of the compound. The inhibitory effect of the adenoid derivative on the growth of MM. 1S human multiple myeloma cells, and the results of the statistical experiment of Graphpad Prism 5, the GI50 of the compound were calculated according to the cell survival rate. The results showed that the yield of 8-bromo-2-amino-2 '-deoxyadenine was 87%. The yield of the adeno-and 2-amino-2 '-deoxyadeno-substituted reaction is 76-95%; the yield of the 2'-deoxy-heteroornithine derivative is 52-70%; all the compounds are analyzed by 1HNMR and 13C-NMR and high-resolution mass spectrum to determine the structure. the 2-amino-2 '-deoxyadeno-1 and 2'-deoxy-isoornithine-substituted 2-amino-2 '-deoxyadeno-1 and 2'-deoxy-isophorone derivatives have obvious fluorescence, the fluorescence intensity of the 2 '-deoxy-isoornithine derivative is sensitive to the environment, different excitation wavelengths and emission wavelengths and different fluorescence intensities are present in the dioxane and the water, At the same time,2 '-deoxy-isoornithine is sensitive to p H, and can be weakened with the increase of p H; compared with 2'-deoxy-bird's, the p-Ka value of the 8-position alkynylin derivative has a significant change; The anti-tumor activity test showed that the 2-amino-2 '-deoxyadeno-1 and 2'-deoxy-I-2 '-deoxy-I-1 compounds substituted by the benzalkynes inhibited the proliferation of MM.1S, and the GI50 of the compounds 2a, 2c,4, 4a, 4b, and 4c was 24.28, 21.11, 7.87, 13.78, 10.08, 7.10. Conclusion: Under the aid of microwave, A series of new 8-position alkynyl-substituted 2-amino-2 '-deoxyadeno-1 and deoxy-isoornithine are synthesized in a high yield. The 8-position is substituted with an aromatic alkynyl group of 2-amino-2'-pentadenoid, and the 2 '-deoxy heteroornithine can produce significant fluorescence. In which,8-position arginylation of 2 '-deoxy-isophorone fluorescent molecule is sensitive to the micro-environment and has the prospect as a fluorescent probe.
【學(xué)位授予單位】：成都醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914
本文編號(hào)：2497813
[Abstract]:Purpose: The nuclear antigen is a basic component of a nucleic acid (DNA or RNA). The nuclear antigen derivative is widely used in the fields of drug development, molecular probe design, cancer mechanism and the like, and is also an anti-metabolic drug commonly used in clinic, such as anti-virus, anti-tumor and the like. The base and the glycosyl of the nuclear antigen can be chemically modified. The modification site of the base has many modification sites, and the C-8-position modification of the methotrexate core is an important way to synthesize the nuclear antigen derivative, and is also an effective method for obtaining the fluorescent nuclear antigen analog. At present, the 8-bit modification of the 2-amino-2 '-deoxyadeno-and 2'-deoxy-avirences is less, and the study is intended to be modified at the 8-bit of the 2-amino-2 '-deoxyadeno-and 2'-deoxy-iopterin, with a view to obtaining a new methotrexate core with anti-tumor activity and which can be used as a fluorescent probe. Method: The preparation of a compound is an important intermediate of base modification. firstly, dissolving 2-amino-2 '-deoxyadenine in glacial acetic acid, adding sodium acetate, dripping an appropriate amount of bromine, and synthesizing 8-bromo-2-amino-2'-deoxyadenine, then, reacting with Sonogashira, dissolving in DMF solution, adding Pd (PPh3) 2Cl2/ Cu I (1:2), Triethylamine (3 eq) and corresponding substituted acetylenic hydrocarbon, microwave heating, synthesis of a series of new 8-bit alkynyl-substituted 2-amino-2 '-ethanal derivatives; the same method, with 8-bromothymol as a precursor, A series of 8-substituted adenine derivatives are also synthesized. The novel 8-position alkynyl-substituted 2-amino-2 '-deoxyadenine derivative is converted into a diazonium salt intermediate by the generation of a diazonium salt intermediate under the action of acetic acid and Na NO2, The fluorescence spectrum, the fluorescence quantum efficiency and the solvent polarity (dioxane, The influence of the value of methanol and water) and solution p h (1.5 -12) on the fluorescence spectrum of the compound. The inhibitory effect of the adenoid derivative on the growth of MM. 1S human multiple myeloma cells, and the results of the statistical experiment of Graphpad Prism 5, the GI50 of the compound were calculated according to the cell survival rate. The results showed that the yield of 8-bromo-2-amino-2 '-deoxyadenine was 87%. The yield of the adeno-and 2-amino-2 '-deoxyadeno-substituted reaction is 76-95%; the yield of the 2'-deoxy-heteroornithine derivative is 52-70%; all the compounds are analyzed by 1HNMR and 13C-NMR and high-resolution mass spectrum to determine the structure. the 2-amino-2 '-deoxyadeno-1 and 2'-deoxy-isoornithine-substituted 2-amino-2 '-deoxyadeno-1 and 2'-deoxy-isophorone derivatives have obvious fluorescence, the fluorescence intensity of the 2 '-deoxy-isoornithine derivative is sensitive to the environment, different excitation wavelengths and emission wavelengths and different fluorescence intensities are present in the dioxane and the water, At the same time,2 '-deoxy-isoornithine is sensitive to p H, and can be weakened with the increase of p H; compared with 2'-deoxy-bird's, the p-Ka value of the 8-position alkynylin derivative has a significant change; The anti-tumor activity test showed that the 2-amino-2 '-deoxyadeno-1 and 2'-deoxy-I-2 '-deoxy-I-1 compounds substituted by the benzalkynes inhibited the proliferation of MM.1S, and the GI50 of the compounds 2a, 2c,4, 4a, 4b, and 4c was 24.28, 21.11, 7.87, 13.78, 10.08, 7.10. Conclusion: Under the aid of microwave, A series of new 8-position alkynyl-substituted 2-amino-2 '-deoxyadeno-1 and deoxy-isoornithine are synthesized in a high yield. The 8-position is substituted with an aromatic alkynyl group of 2-amino-2'-pentadenoid, and the 2 '-deoxy heteroornithine can produce significant fluorescence. In which,8-position arginylation of 2 '-deoxy-isophorone fluorescent molecule is sensitive to the micro-environment and has the prospect as a fluorescent probe.
【學(xué)位授予單位】：成都醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914
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