本文選題：抗腫瘤 + DNA靶向　； 參考：《大連理工大學(xué)》2016年碩士論文

【摘要】：根據(jù)分子雜交的設(shè)計(jì)思想,本文從不同的DNA嵌入劑母體出發(fā),引入吲哚、異喹啉作為藥效團(tuán),設(shè)計(jì)合成三個(gè)系列新型DNA靶向抗腫瘤藥物分子,確認(rèn)化合物的分子結(jié)構(gòu),通過(guò)光譜測(cè)試、體外抗腫瘤活性等探究化合物與DNA之間的相互作用。以9,10-菲醌為原料,基于其本身的生物活性和吲哚類衍生物的抗腫瘤作用,設(shè)計(jì)合成6個(gè)含吲哚取代基的菲并[9,10-d]咪唑類衍生物,MS、1HNMR、13CNMR和單晶衍射等驗(yàn)證分子結(jié)構(gòu)正確,并證實(shí)該系列分子具有大的近平面共軛結(jié)構(gòu)。紫外吸收光譜、熒光光譜、圓二色譜、粘度測(cè)試等表明該系列化合物可以與DNA結(jié)合,引起DNA雙螺旋結(jié)構(gòu)的改變。體外抗腫瘤活性測(cè)試表明,該系列化合物能夠有效地于微摩爾濃度抑制MCF-7、BGC-823腫瘤細(xì)胞增殖。以4-溴1,8-萘酐為原料,引入異喹啉作為藥效團(tuán),設(shè)計(jì)合成4個(gè)含有異喹啉取代基的萘酰亞胺類衍生物。經(jīng)MS和1HNMR、13CNMR等驗(yàn)證分子結(jié)構(gòu)正確。通過(guò)分子與DNA作用前后的紫外、熒光、圓二色、離子效應(yīng)、粘度測(cè)試等表明該系列分子能夠與DNA結(jié)合,引起DNA構(gòu)象轉(zhuǎn)變,DNA鏈解旋松弛。體外抗腫瘤活性測(cè)試表明,該系列化合物對(duì)于MCF-7、BGC-823腫瘤細(xì)胞具有顯著的抑制增殖作用。以4-溴-1,8-萘酐為原料,基于在萘酰亞胺母體上并入可以增大分子共軛面積的芳香環(huán)可增強(qiáng)分子DNA嵌入能力的研究基礎(chǔ),設(shè)計(jì)合成了4個(gè)N-取代-咪唑并萘酰亞胺類衍生物。經(jīng)由MS和1HNMR、13CNMR等驗(yàn)證分子結(jié)構(gòu)正確。利用紫外、熒光、圓二色譜、離子效應(yīng)、粘度測(cè)試等探究該系列化合物與DNA的作用模式。MTT比色法探究化合物體外抗腫瘤活性,表明該系列化合物可以在微摩爾濃度顯著抑制腫瘤細(xì)胞增殖,其中化合物Z2對(duì)于所選細(xì)胞株的抑制活性最大,其對(duì)BGC-823的IC50值為8.23μM。
[Abstract]:According to the design idea of molecular hybridization, three series of novel DNA targeted antitumor drug molecules were designed and synthesized by introducing indole and isoquinoline as pharmacophore from different DNA intercalant parent, and the molecular structure of the compounds was confirmed. The interaction between the compounds and DNA was investigated by spectroscopic test and in vitro anti-tumor activity. Based on its biological activity and the anti-tumor effect of indole derivatives, six phenanthroline derivatives containing indole-substituted group were designed and synthesized. It is confirmed that this series of molecules have large near plane conjugate structures. UV absorption spectrum, fluorescence spectrum, circular dichroism chromatography and viscosity measurement show that the series of compounds can bind to DNA and cause the change of double helix structure of DNA. The antitumor activity test in vitro showed that this series of compounds could effectively inhibit the proliferation of MCF-7 BGC-823 tumor cells at the micromolar concentration. Four naphthalimide derivatives containing isoquinoline substituents were designed and synthesized by using 4-bromo-1-buta-8-naphthalic anhydride as raw material and isoquinoline as pharmacophore. The molecular structure was confirmed by MS and 1HN MR13 CNMR. The UV, fluorescence, circular dichroism, ion effect and viscosity test show that the series of molecules can bind to DNA and cause the conformational transition of DNA to despin relaxation of DNA strand by UV, fluorescence, circular dichroism, ion effect and viscosity test. The antitumor activity test in vitro showed that this series of compounds could significantly inhibit the proliferation of MCF-7 BGC-823 tumor cells. Four N-substituted imidazole-naphthalimide derivatives were designed and synthesized from 4-bromo-1-butadiene-8-naphthalic anhydride. Four N-substituted imidazole-naphthalimide derivatives were designed and synthesized on the basis of the addition of aromatic rings on the base of naphthalene imide matrix to enhance the intercalation ability of the molecular DNA. The molecular structure was verified by MS and 1HN MR13 CNMR. UV, fluorescence, circular dichroism, ion effect and viscosity test were used to explore the interaction mode of this series of compounds with DNA. MTT colorimetric method was used to explore the antitumor activity of the compounds in vitro. The results showed that the series of compounds could significantly inhibit the proliferation of tumor cells at the micromolar concentration. The inhibitory activity of compound Z2 on the selected cell line was the highest, and the IC50 value of compound Z2 to BGC-823 was 8.23 渭 M.
【學(xué)位授予單位】：大連理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：O626

【參考文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前3條

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2 趙雯雯;含三氮唑雜環(huán)化合物的合成及生物活性研究[D];大連理工大學(xué);2009年

3 徐欣怡;異喹啉生物堿衍生物的制備和抗腫瘤活性的研究[D];西南交通大學(xué);2006年

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本文編號(hào)：1964300