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  本文關(guān)鍵詞：α-甲基查爾酮類衍生物的合成及抗宮頸癌活性研究　出處：《新疆醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 查爾酮異甘草素 Claisen-Schmidt反應(yīng) 微波固相反應(yīng) 抗宮頸癌活性 α、β不飽和羰基

【摘要】：目的:1.采用不同催化方法合成分離查爾酮類化合物異甘草素并分析各自優(yōu)缺點。2.分析查爾酮類化合物異甘草素結(jié)構(gòu)中α、β不飽和羰基在生物活性中的作用。3.設(shè)計合成及分離α-甲基查爾酮。4.對上述α-甲基查爾酮類衍生物分別評價其對抑制子宮頸癌細胞的細胞增殖和促進癌細胞凋亡作用。5.通過分子對接的方法對α-甲基查爾酮衍生物進行分子學(xué)上的研究。方法:1.利用經(jīng)典Claisen-Schmidt反應(yīng),采用SOCl2/EtOH、KF/Al2O3配合超聲及KOH/Al2O3配合微波三個催化條件合成查爾酮類異甘草素并進行結(jié)構(gòu)表征。2.對SOCl2/EtOH、KF/Al2O3配合超聲及KOH/Al2O3配合微波這三種催化條件合成異甘草素的產(chǎn)率、合成時間進行統(tǒng)計比較得出較優(yōu)的合成條件。3.以相應(yīng)的苯丙酮衍生物和苯甲醛衍生物為原料,以哌啶/無水乙醇為催化劑合成α-甲基查爾酮。4.以SiHa(人子宮頸鱗癌細胞)和HeLa(子宮頸癌細胞)細胞株作為體外模型,利用MTT法對目標(biāo)化合物進行抗宮頸癌細胞增殖的活性的研究。5.以SiHa(人子宮頸鱗癌細胞)和HeLa(子宮頸癌細胞)細胞株作為體外模型利用流式細胞儀測定目標(biāo)化合物對宮頸癌細胞促凋亡作用。6.運用分子對接技術(shù)將目標(biāo)化合物與分子蛋白進行分子學(xué)上的研究。結(jié)果:1.以SOCl2/EtOH為催化劑合成異甘草素,產(chǎn)率在47.2%~80.6%之間,而反應(yīng)產(chǎn)率對應(yīng)的時間在1-4 h之間;KF/Al2O3配合超聲為催化條件合成異甘草素,產(chǎn)率在12.1%-95.6%之間,然而產(chǎn)率的高低與其超聲的時間跟超聲的功率有關(guān),最大產(chǎn)率是在超聲功率為250 W的條件下超聲30 min得到的;KOH/Al2O3配合微波為催化條件合成異甘草素,其結(jié)構(gòu)經(jīng)1H-NMR、13C-NMR譜確認,產(chǎn)率在10.3%-93.5%之間。同樣,產(chǎn)率與微波的時間及微波功率有關(guān),但并不是功率越高產(chǎn)率也越大,在微波功率150 W,微波時間為100 s時反應(yīng)的產(chǎn)率最高。2.以相應(yīng)的苯丙酮衍生物和苯甲醛衍生物為原料,以哌啶/無水乙醇為催化劑合成15個α-甲基查爾酮衍生物,其結(jié)構(gòu)1H-NMR確認,產(chǎn)率在30.2%-65.9%之間。3.對合成的15個α-甲基查爾酮衍生物進行抗宮頸癌活性研究,利用MTT法考察目標(biāo)化合物的抗宮頸癌細胞增殖的活性研究,其中IC50最低的是化合物3(0.035μM),(E)-1-(2,4-二羥苯基)-3-(4-二甲氨苯基)-2-甲基丙烯酮,對宮頸癌SiHa細胞的抑制活性。4.化合物3的濃度為1μg.ml-1、2μg.ml-1、4μg.ml-1時對宮頸癌SiHa的早期凋亡率分別為11.5%、32.5%、38.2%,對宮頸癌HeLa細胞的早期凋亡率分別為11.8%、31.2%、43.8%。5.將目標(biāo)化合物3與蛋白質(zhì)(PDB:3E47)進行分子對接,化合物3的酚羥基和羰基氧可以和20S Proteasome結(jié)合口袋內(nèi)的多個氨基酸殘基形成氫鍵作用。參與形成氫鍵的殘基包括THR1、THR21、GLY47和SER129。同時我們測定了各氫鍵所在重原子間的距離,發(fā)現(xiàn)所形成的氫鍵中有4個為較強氫鍵(距離在2.5-3.0?范圍內(nèi))。這些氫鍵作用是藥化合物3和20S Proteasome蛋白的結(jié)合的主要驅(qū)動力之一。結(jié)論:通過三中不同的催化條件合成甘草查爾酮類化合物,并且對其目標(biāo)化合物進行結(jié)構(gòu)鑒定;α-甲基查爾酮類化合物對Si Ha細胞和HeLa細胞表現(xiàn)出較顯著的抑制活性和促進凋亡作用;得到較強的抑制宮頸癌細胞增殖和促宮頸癌細胞凋亡作用的化合物3。并從分子學(xué)的角度解釋了α-甲基查爾酮類化合物顯著的抑制有絲分裂的作用。此結(jié)果對從甘草查爾酮異甘草素類衍生物中篩選出具有抗子宮頸癌的有效候選藥物奠定重要的基礎(chǔ)。
[Abstract]:Objective: using 1. different catalytic synthesis methods for separation of chalcones isoliquiritigenin and.2. analysis to analyze the advantages and disadvantages of chalcones isoliquiritigenin structure alpha, beta unsaturated carbonyl in the biological activity of the role of.3. synthesis and separation of alpha methyl chalcone.4. of the alpha methyl chalcone derivatives were evaluated the inhibition of cervical cancer cell proliferation and promote apoptosis of cancer cell.5. by molecular docking method of alpha methyl chalcone derivatives for molecular research. Methods: 1. by using the classical Claisen-Schmidt reaction, using SOCl2/EtOH, KF/Al2O3 and KOH/Al2O3 combined with ultrasonic microwave combined with three catalytic conditions for synthesis of chalcones and isoliquiritigenin structural characterization of.2. on SOCl2/EtOH, KF/Al2O3 and KOH/Al2O3 combined with ultrasonic microwave yield the three catalytic conditions of synthesis of isoliquiritigenin synthesis. The time for statistical comparisons between.3. synthesis was optimized with benzene acetone derivatives and corresponding benzaldehyde derivatives as raw materials, piperidine / ethanol as catalyst for synthesizing alpha methyl chalcone.4. in SiHa (human cervical squamous cell carcinoma (HeLa) and cervical cancer cells) cells as in vitro model,.5. study anti cervical cancer cell proliferation of target compounds by MTT method with SiHa (activity of human cervical squamous cell carcinoma (HeLa) and cervical cancer cells) cells as an in vitro model using flow cytometry on cervical cancer cell apoptosis.6. using molecular docking technology will target compounds and molecular protein molecular research the target compounds. Results: 1. to SOCl2/EtOH for the synthesis of isoliquiritin catalyst, yield between 47.2%~80.6%, and the reaction yield corresponding time in 1-4 h; KF/Al2O3 combined with ultrasonic catalytic The synthesis conditions of isoliquiritigenin, yield between 12.1%-95.6%, but the power yield and ultrasonic time and ultrasonic, the maximum yield is 250 W under the condition of ultrasound in 30 min ultrasonic power; KOH/Al2O3 combined with microwave catalytic conditions for synthesis of isoliquiritigenin, characterized by 1H-NMR, 13C-NMR spectra confirmed that the yield of 10.3%-93.5%. Also, the time and the yield of microwave power and microwave power, but not the more productive rate is larger, the microwave power 150 W, microwave time is 100 s when the highest yield of.2. reaction with benzene acetone derivatives and corresponding benzaldehyde derivatives as raw material, anhydrous ethanol / piperidine as catalyst synthesis of 15 alpha methyl chalcone derivatives, the structure of 1H-NMR confirmed that the yield of.3. was studied in 15 cervical cancer activity of anti alpha synthesis of methyl chalcone derivatives at 30.2%-65.9%, examined using MTT method Anti cervical cancer cells proliferation activity of the target compounds, of which IC50 is the lowest of 3 compounds (0.035 M), (E) -1- (2,4- dihydroxy phenyl) -3- (4- two ammonia nitrogen phenyl) -2- methyl acrylic ketone compounds, the inhibitory activity of.4. on human cervical cancer cell line SiHa 3 concentration of 1 g.ml-1,2 g.ml-1,4 g.ml-1 of SiHa cervical cancer and early apoptosis rate were 11.5%, 32.5%, 38.2%, on cervical cancer HeLa cell early apoptosis rate were 11.8%, 31.2%, 43.8%.5. to 3 target compounds and protein (PDB:3E47) by molecular docking, 3 compounds of phenol hydroxyl and carbonyl oxygen and 20S combined with Proteasome in the pocket of a plurality of amino acid residues to form hydrogen bonds. Residues involved in the formation of hydrogen bonds including THR1, THR21, GLY47 and SER129. at the same time, we measured the distance between the heavy atoms of hydrogen bonds, found by the formation of hydrogen bonds in 4 for the strong hydrogen bonds (the distance in 2.5-3.0? Range). These hydrogen bonding is one of the main driving force of drug compounds with 3 and 20S Proteasome protein. Conclusion: the catalytic conditions of three different synthetic licorice chalcone compounds, and identify the structure of the target compound; alpha methyl chalcone compounds on Si Ha cells and HeLa cells showed inhibition the activity was significantly and apoptosis; proliferation of cervical cancer cells by compound strong and promote cervical cancer cell apoptosis and 3. from molecular explanation for the alpha methyl chalcone compounds significantly inhibit the mitogenic effect. The results of the Licochalcone isoliquiritigenin derivatives in screening the foundation of effective drug candidate has against cervical cancer.

【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914;R96

【參考文獻】

相關(guān)期刊論文 前4條

1 張晶;楊靜;湯宏斌;;異甘草素對人宮頸癌細胞增殖的抑制作用[J];中國藥理學(xué)與毒理學(xué)雜志;2005年06期

2 劉因華;;抗腫瘤藥物的研究現(xiàn)狀與發(fā)展前景[J];中國醫(yī)藥指南;2007年S1期

3 古扎麗努爾·阿不力孜;程靜新;米克熱木;古蘭丹;李華;米合日尼沙;米日古麗;米日古麗·艾乃土;路玲;;新疆維吾爾族婦女宮頸癌的HPV譜研究[J];腫瘤;2007年05期

4 陳日來;李玉珍;李成;;異甘草素的研究進展[J];臨床醫(yī)藥實踐雜志;2008年13期

相關(guān)碩士學(xué)位論文 前1條

1 王志強;異甘草素抗腫瘤血管生成的作用研究[D];蘭州大學(xué);2012年

，

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