2-腈基-3-取代苯基丙烯酸类衍生物的合成及生物活性研究
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摘要
抗癌药物的研究具有重要的理论意义和应用前景。本论文研究2-腈基-3-取代苯基丙烯酸类化合物的合成及其生物活性。
首先发展了用DCC偶联法用腈代乙酸与胺类化合物合成腈代乙酰胺的新方法，共合成10种化合物，收率51-90％操作简便，收率较高是一种较好的合成方法
应用克脑文盖尔(Knovevenagel)缩合，由五种取代苯甲醛与腈代乙酸(酯)合成了5种2-腈基-3-取代苯基丙稀酸(酯)，收率43.1-95％。由取代苯甲醛与腈代乙酰胺合成了10种2-腈基-3-取代苯基丙稀酰胺，收率42-95％。其中四种为新化合物。其结构由IR、MS、NMR、及元素分析表征。一种酰胺(zxm-12)的构型通过x-光单晶衍射法测之为E式。
所合成的化合物均测定了抗乙酰胆碱酯酶活性。结果表明它们在2.05×10~(-5)mol／L时有一定的活性，但活性较弱。测定了它们对人胃癌细胞(BGC-823)、人肝癌细胞(KB-7402)和人肝癌细胞(BEL-7402)的抑制活性，结果显示部分化合物具有一定的活性。其IC50为1.62-17.5×10~(-5)mol／ml。
表明在适当的取代苯基和取代胺基配合下，此类化合物可能具有抗癌活性，为进一步的研究工作提供了基础。
It's very important to research new antitumor drugs, It has academic significance and possibility to widely applicate. This paper disclosed the research on the synthesis and biological activities of 2-cyano-3-substitued-phenylacrylic acid derivatives.
In this paper a new preparation method for N-substituded cyanoacetamides using cyanoacetic acid and N-substituded amine as materials through DCC coupling was developed. And 10 compounds have been synthesized , with yield 51-90%. The results show that This procedure possesses characters of convenient operation and higher yield and is suitable for preparation of cyanoacetamides of different amine.
Using Knoevenagel condensation, 5 2-cyano-3-substituedphenyl acrylic acid (esters) have been prepared using substituded benzaldehydes and cyanoacetic acid(esters), yield 43.1-95%. And using five substituded benzaldehydes and cyanoaceticamides, 15 compounds including 4 new compounds 2-cyano-3-substituedphenylacrylamide have been synthesized with yield 42-95%. And the synthesized compounds were characterized by IR, ~1H NMR MS and EA. The configuration of the compound(zxm-12) been determined by single crystal diffraction. It is (E) form
The anti-biological activities of acetylcholine enzyme for compounds have all been tested. And it is showed that there are some activities in concentrate of 2.05x10~(-5)mol/L, but it is not strong. The anti-tumor 1 activities of those compound for human stomach cancer(BGC-823)、liver cancer (KB-7402) and liver cancer (BEL-7402) cell were tested. And as a result, some compounds have weak-middle activities with IC_(50) 1.62-17.5x10~(-5) mol/ml. It is evident from the result this kinds of compounds could have better anti-tumor activities if substituted-phenyl and substituted amide are used proper. It is provided base for further studying.
首先发展了用DCC偶联法用腈代乙酸与胺类化合物合成腈代乙酰胺的新方法，共合成10种化合物，收率51-90％操作简便，收率较高是一种较好的合成方法
应用克脑文盖尔(Knovevenagel)缩合，由五种取代苯甲醛与腈代乙酸(酯)合成了5种2-腈基-3-取代苯基丙稀酸(酯)，收率43.1-95％。由取代苯甲醛与腈代乙酰胺合成了10种2-腈基-3-取代苯基丙稀酰胺，收率42-95％。其中四种为新化合物。其结构由IR、MS、NMR、及元素分析表征。一种酰胺(zxm-12)的构型通过x-光单晶衍射法测之为E式。
所合成的化合物均测定了抗乙酰胆碱酯酶活性。结果表明它们在2.05×10~(-5)mol／L时有一定的活性，但活性较弱。测定了它们对人胃癌细胞(BGC-823)、人肝癌细胞(KB-7402)和人肝癌细胞(BEL-7402)的抑制活性，结果显示部分化合物具有一定的活性。其IC50为1.62-17.5×10~(-5)mol／ml。
表明在适当的取代苯基和取代胺基配合下，此类化合物可能具有抗癌活性，为进一步的研究工作提供了基础。
It's very important to research new antitumor drugs, It has academic significance and possibility to widely applicate. This paper disclosed the research on the synthesis and biological activities of 2-cyano-3-substitued-phenylacrylic acid derivatives.
In this paper a new preparation method for N-substituded cyanoacetamides using cyanoacetic acid and N-substituded amine as materials through DCC coupling was developed. And 10 compounds have been synthesized , with yield 51-90%. The results show that This procedure possesses characters of convenient operation and higher yield and is suitable for preparation of cyanoacetamides of different amine.
Using Knoevenagel condensation, 5 2-cyano-3-substituedphenyl acrylic acid (esters) have been prepared using substituded benzaldehydes and cyanoacetic acid(esters), yield 43.1-95%. And using five substituded benzaldehydes and cyanoaceticamides, 15 compounds including 4 new compounds 2-cyano-3-substituedphenylacrylamide have been synthesized with yield 42-95%. And the synthesized compounds were characterized by IR, ~1H NMR MS and EA. The configuration of the compound(zxm-12) been determined by single crystal diffraction. It is (E) form
The anti-biological activities of acetylcholine enzyme for compounds have all been tested. And it is showed that there are some activities in concentrate of 2.05x10~(-5)mol/L, but it is not strong. The anti-tumor 1 activities of those compound for human stomach cancer(BGC-823)、liver cancer (KB-7402) and liver cancer (BEL-7402) cell were tested. And as a result, some compounds have weak-middle activities with IC_(50) 1.62-17.5x10~(-5) mol/ml. It is evident from the result this kinds of compounds could have better anti-tumor activities if substituted-phenyl and substituted amide are used proper. It is provided base for further studying.
引文
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10 Chen, Wen-Kang; Tsai Chia-Fong; Liao Pel-Hu; Lee, Yean-Jang.Synthesis of Caffeic Acid Esters as Antioxidants by Esterification via Acyl Chlorides, Chin. Pharm. J., 1999, 51(4), 271-277.
11 Grunberger, D.; Banerjee, R.; Eisinger, K.; Oltz, E.M.; Efros, L.;Caldwell, M.; Estevez, V.; Nakanishi, K.. Preferential Cytotoxicity on Tumor Cells by Caffeic Acid Phenylethyl Ester Isolated from Propolis, Experientia, 1988, 44, 230-232.
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3 玄红专；胡福良；顾美儿。食品研究与开发，蜂胶中咖啡酸苯乙酯的研究进展2006，5(27)
4 Grunberger,D.; Banerjee, R.; Eisinger,K.; oltz, E.M.; Efros, L.; Caldwell, M.; Estevez, V.;Nakanishi, K.. Prefential Cytotoxicity on Tumor Cells by Caffeic Acid Phenylethyl Ester Isolated from Propolis, Experientia, 1988, 44, 230-232.
5 Greenaway W.; Whatley F.R. Synthesis of Esters of Acetyloxycaffeic Acids and Their Occurrence in Poplar Bud Exudates. Journal of Chromat-ography, 1991, 54, 3113-3121.
6 Eisinger, M.; Marko, 0.; Shun-Ichiro, 0. Growth Regulation of Human Melanocytes Mitogenic Factor in Extracts of Melanomn, Astrocytoma, and Fibroblast Cell Lines, Science, 1985, 229, 984.
7 Cizmarik J.; Matel I. Propolis, A Remarkable Hive Product. Apimondia Publishing House, Bucharest, Romania, 1978, 30-31.
8 Natarajan, K.; Singh, S.; Burke, Jr., T.R. Caffeic Acid Phenylethyl Ester Is A Potent and Specific Inhibitor of Activation of Nuclear Transcription Factor NF-k B], Proc. Natl. Acad. Sci. USA, 1996, 93,9090-9095.
9 Hladon B. In Vitro Studies on the Cytostatic Activity of Propolis Extracts. Drug Rev., 1980, 30(11), 1847-1848.
10 Chen, Wen-Kang; Tsai Chia-Fong; Liao Pel-Hu; Lee, Yean-Jang.Synthesis of Caffeic Acid Esters as Antioxidants by Esterification via Acyl Chlorides, Chin. Pharm. J., 1999, 51(4), 271-277.
11 Grunberger, D.; Banerjee, R.; Eisinger, K.; Oltz, E.M.; Efros, L.;Caldwell, M.; Estevez, V.; Nakanishi, K.. Preferential Cytotoxicity on Tumor Cells by Caffeic Acid Phenylethyl Ester Isolated from Propolis, Experientia, 1988, 44, 230-232.
12 Burdock G.A. Review of the Biological Properties and Toxicity of Bee Propolis, Food Chem. Toxicol., 1998, 36, 347-63.
13 range J.M.; Davey R.W. Antibacterial Properties of Propolis. J.R. Soc. Med., 1990, 83, 159-160.
14 cells, F.B. A Review of the Antimicrobial Effects of Propolis. Am. Bee. J., 1979, 60, 59-65.
15 Son S.; Lewis, B. A. Free Radical Scavenging and Antioxidative Activity of Caffeic Acid Amide and Ester Analogues: Structure- Activity Relationship. J. Agric. Food. Chem., 2002, 50, 486-472.
16 Su Z. Z.; Lin, J.; Grunberger, D.; Fisher, P.B. Growth Suppression and Toxicity Induced by Caffeic Acid Phenylethyl Ester (CAPE) in Type 5 Adenovirus-transform Rat Embryo Cells Correlate Directly with Transformation Progression, Caner Res., 1994, 54, 1865-1870.
17 Frenkel K.; Wei H.; Bhimani R.; Ye J.; Zadunaiasky J.A.; Huang M.T.; Ferraro T.; Conny A.H.; Grunberger D.. Inhibitor of Tumor Promotermediated Processes in Mouse Skin and Bovine Lens by Caffeic Acid Phenylethyl Ester, Cancer Rev., 1993, 63, 1255-1261
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