發(fā)布時(shí)間：2018-03-12 19:01

  本文選題：4H-吡喃　切入點(diǎn)：喹喔啉衍生物　出處：《遼寧大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：含氧、氮芳雜環(huán)化合物被廣泛應(yīng)用于抗腫瘤、抗菌劑,抗病毒,消炎方面,已經(jīng)成為當(dāng)今新藥研究的熱門領(lǐng)域,其中4-芳基-4H-吡喃類及喹喔啉類有其各自特有的抗菌、抗腫瘤機(jī)制,天然產(chǎn)物中已發(fā)現(xiàn)的4-芳基-4H-吡喃類衍生物能夠與腫瘤細(xì)胞的秋水仙素位點(diǎn)或鄰近位點(diǎn)結(jié)合,從而抑制微管蛋白活性,導(dǎo)致腫瘤凋亡。本論文第一章運(yùn)用骨架躍遷原理和局部修飾原理,以4-芳基-苯并吡喃母核為先導(dǎo)化合物,設(shè)計(jì)了4H-吡喃類化合物。本文以取代苯甲醛,和丙二腈經(jīng)經(jīng)克腦文格爾反應(yīng),合成芳基甲叉基丙二腈,再與β-酮基酯環(huán)合得到目標(biāo)化合物。共合成25個(gè)4H吡喃類衍生物20a-20j以及21a-21o,結(jié)構(gòu)經(jīng)IR,1H-NMR的確認(rèn),部分化合物同時(shí)經(jīng)過(guò)13C-NMR,MS結(jié)構(gòu)確認(rèn)。采用MTT法,測(cè)定了4H-吡喃類目標(biāo)化合物20a、20b、20c、20d、20e、20f、20g、20h、21b、21c和21n對(duì)人肝癌細(xì)胞BL7402的抗腫瘤活性。其中9個(gè)化合物的活性優(yōu)于陽(yáng)性對(duì)照藥5-Fu,尤其是目標(biāo)產(chǎn)物20b、20g、21b在體外顯示了很好的藥理活性,它們對(duì)BL7402的IC50值分別為24.04μmol/L、38.20μmol/L、21.3μmol/L,分別是陽(yáng)性對(duì)照藥的5.75倍、1.61倍、6.47倍,初步分析了該類衍生物的構(gòu)效關(guān)系。另外,論文以為5-氟-2硝基苯胺為起始原料,經(jīng)芳環(huán)的親核取代,得到5-L-脯氨醇-2硝基苯胺,再經(jīng)Pd/C-甲酸銨還原,得到4-L-脯氨醇鄰苯二胺,然后與α-氯-取代苯乙酮環(huán)合,得到喹喔啉母核,再與酸經(jīng)縮合得到目標(biāo)化合物。共8個(gè)化合物均經(jīng)過(guò)紅外光譜以及1H-NMR結(jié)構(gòu)確認(rèn),并從中選取4個(gè)目標(biāo)產(chǎn)物做抗菌活性測(cè)定。
[Abstract]:Aromatic heterocyclic compounds containing oxygen and nitrogen have been widely used in anti-tumor, antimicrobial, antiviral and anti-inflammatory fields, and have become a hot field in the research of new drugs. Among them, 4-aryl-4H-pyrans and quinoxaline have their own unique antibacterial properties. Antitumor mechanism, 4-aryl-4H-pyran derivatives found in natural products can bind to colchicine sites or adjacent sites of tumor cells, thereby inhibiting tubulin activity. In chapter 1, we use the skeleton transition principle and the local modification principle to design 4H-pyran compounds with 4-aryl-benzopyran parent nucleus as the lead compounds. Aryl methyl malonitrile was synthesized from malonitrile by Knovinger reaction, and then cyclized with 尾 -keto ester to obtain the target compound. A total of 25 4H pyran derivatives 20a-20j and 21a-21owere synthesized. The structures were confirmed by IR ~ 1H-NMR. Some of the compounds were confirmed by 13C-NMRMS at the same time. MTT method was used. The antitumor activities of 4H-pyran target compounds 20aHX 20bn20cn20dCn20eO20fFN 20fU 20htbc21c and 21n on human hepatoma cell line BL7402 were determined. The activities of 9 of them were superior to those of positive control drug 5-Fu.In particular, the target product 20bn20g21b showed a good pharmacological activity in vitro, and the antitumor activity of 4H-pyran group was better than that of 5-Fu.In particular, the target product, 20bng21b, showed a good pharmacological activity in vitro. Their IC50 values to BL7402 were 24.04 渭 mol / L ~ 38.20 渭 mol / L ~ 21.3 渭 mol 路L ~ (-1), respectively, which were 5.75 times, 1.61 times and 6.47 times of that of a positive control drug, respectively. The structure-activity relationship of these derivatives was preliminarily analyzed. 5-L-proline 2-nitroaniline was synthesized, then reduced by PD / C- ammonium formate to obtain 4-L-proline o-phenylenediamine, then cyclized with 偽 -chloro-substituted acetophenone to obtain quinoxaline mother nucleus. The eight compounds were confirmed by IR and 1H-NMR, and four of them were selected for the determination of antimicrobial activity.
【學(xué)位授予單位】：遼寧大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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