槲皮素酯的合成及其抗肿瘤活性研究
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摘要
槲皮素是一种具有多种生物活性的黄酮类化合物,可以预防和治疗肿瘤及心血管疾病。以槲皮素为先导物,合成了7个标题化合物,其中6个未见文献报道,目标产物结构经IR、~1HNMR、ESI-MS确证。采用MTT法,初步评价了7个目标化合物对人食管鳞癌细胞EC109、人食管鳞癌细胞EC9706、人胃癌细胞SGC7901及小鼠黑色素瘤细胞B16-F10这4株肿瘤细胞的体外增殖抑制作用。结果显示,槲皮素五乙酸酯对EC109和EC9706细胞抑制作用明显优于母药槲皮素和5-FU,是一个很有潜力的新型抗肿瘤候选化合物。
Quercetin is a kind of flavonoids with a variety of biological activity,which can prevent and cure tumor and cardiovascular diseases.Seven quercetin esters were synthesized with quercetin as the leader.Six of them were not reported in the literature.The structures were confirmed by IR,~1HNMR and ESI-MS.The MTT assay was used to evaluate the in vitro proliferation of seven tumor cells in vitro against human esophageal squamous carcinoma cell line EC109,human esophageal squamous carcinoma cell line EC9706,human gastric cancer cell line SGC7901 and mouse melanoma cell line B16-F10.The results showed that quercetin pentaacetate is a novel and potential antitumor candidate compound with significantly superior inhibitory activity to quercetin and 5-FU on EC109 and EC9706 cells.
Quercetin is a kind of flavonoids with a variety of biological activity,which can prevent and cure tumor and cardiovascular diseases.Seven quercetin esters were synthesized with quercetin as the leader.Six of them were not reported in the literature.The structures were confirmed by IR,~1HNMR and ESI-MS.The MTT assay was used to evaluate the in vitro proliferation of seven tumor cells in vitro against human esophageal squamous carcinoma cell line EC109,human esophageal squamous carcinoma cell line EC9706,human gastric cancer cell line SGC7901 and mouse melanoma cell line B16-F10.The results showed that quercetin pentaacetate is a novel and potential antitumor candidate compound with significantly superior inhibitory activity to quercetin and 5-FU on EC109 and EC9706 cells.
引文
[1]翟广玉,颜子童,渠文涛,等.槲皮素——有益于健康的天然化合物[J].食品研究与开发,2015,36(7):119-122.
[2]翟广玉,马海英,郜蕾.槲皮素及其衍生物的抗肿瘤活性研究进展[J].化学试剂,2015,37(2):97-103.
[3]AKIRA M,HITOSHI A,JUNJI T.Multitargeted cancer prevention by quercetin[J].Cancer Lett.,2008,269(2):315-325.
[4]FEDERICO D.Life or death:neuroprotective and anticancer effects of quercetin[J].J.Ethnopharmacol.,2012,143(2):383-396.
[5]DHARAMBIR K,SONAM M,KATRIN S,et al.Molecular mechanisms of action of quercetin in cancer:recent advances[J].Tumor Biol.,2016,37(10):12 927-12 939.
[6]EDWARDS R L,LYON T,LITWIN S E,et al.Quercetin reduces blood pressure in hypertensive subjects[J].J.Nutr.,2007,137(11):2 405-2 411.
[7]SHYAMALA G,ANDREA N F,ADAM T C,et al.Quercetin inhibits rhinovirus replication in vitro and in vivo[J].Antiviral Res.,2012,94(3):258-271.
[8]AGNES W B,GUIDO R M,ALT B.Health effects of quercetin:from antioxidant to nutraceutical[J].Eur.J.Pharmacol.,2008,585(2/3):325-337.
[9]VENGADESHPRABHU K,SOMASUNDARAM A,RAJARAJAN A T,et al.Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis[J].Drug Discov.Today,2016,21(4):632-639.
[10]EDISON O,EDWIN G P,CARLOS A,et al.Why is quercetin a better antioxidant than taxifolin?Theoretical study of mechanisms involving activated forms[J].J.Mol.Model,2013,19(6):2 165-2 172.
[11]ALKA G,KAVITA B,INDIRA R,et al.Quercetin:a wonder bioflavonoid with therapeutic potential in disease management[J].Asian Pac.J.Trop.Dis.,2016,6(3):248-252.
[12]VANESA A M,GABRIELA V F,MATIAS I S,et al.Spectroscopic and thermodynamic study of chrysin and quercetin complexes with Cu(Ⅱ)[J].J.Chem.Eng.Data,2016,61(2):987-995.
[13]HUANG He,JIA Qi,MA Jin-gui,et al.Discovering novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors[J].Eur.J.Med.Chem.,2009,44(5):1 982-1 988.
[14]WANG Xiao-lan,DUAN Yu.Anti-platelet aggregation mechanisms of quercetin fatty acid ester[J].J.Chem.Pharm.Res.,2014,6(6):599-602.
[15]NATASA M,MARTIN S,MARCELA K,et al.Modulation of BV-2 microglia functions by novel quercetin pivaloyl ester[J].Neurochem.Int.,2015,90:246-254.
[16]SATVIR S L,ZIAULLAH Z,VASANTHA H P,et al.Novel quercetin-3-O-glucoside eicosapentaenoic acid ester,ameliorates inflammation and hyperlipidemia[J].Inflammopharmacol,2015,23(4):173-185.
[17]PANAGIOTIS T N,PARASKEVI T,ANASTASIOS P,et al.Novel polyfunctional esters of ibuprofen and ketoprofen with hypolipidemic,lipoxygenase inhibitory and enhanced anti-inflammatory activity[J].Med.Chem.Res.,2017,26(2):461-472.
[18]TAHSIN F K,MARIA V C,MIN-SUNG L E,et al.Rational design and structure-activity relationship studies of quercetin-amino acid hybrids targeting the anti-apoptotic protein Bcl-x L[J].Org.Biomol.Chem.,2017,15(37):7 956-7 976.
[19]MARTINA Z,TEODOR A E,VLADIM K,et al.Effect of3-O-Galloyl substitution on the electrochemical oxidation of quercetin and silybin galloyl esters at glassy carbon electrode[J].Electroanal,2013,25(7):1 621-1 627.
[20]YE Bin,YANG Jin-liang,CHEN Li-juan,et al.Induction of apoptosis by phenylisocyanate derivative of quercetin:involvement of heat shock protein[J].Anti-Cancer Drugs,2007,18(10):1 165-1 171.
[21]SAMOKHVALOV G I,BUDAGYANTS M I,SHAKHOVAM K,et al.7-Alkyl ethers of quercetin and their antioxidant efficiency[J].Russ.Chem.Bull.,1963,12(9):1 475-1 478.
[22]BOUKTAIB M,ATMANI A,ROLANDO C.Regio-and stereoselcetive synthesis of the major metabolite of quercetin,quercetin-3-O-beta-D-glucuronide[J].Tetrahedron Lett.,2002,43(35):6 263-6 266.
[23]EKTA K,HANUMANTHARAO G R,RANJU K,et al.Comparison of the prevention of aflatoxin B1-induced genotoxicity by quercetin and quercetin pentaacetate[J].Bioorg.Med.Chem.Lett.,2002,12(18):2 579-2 582.
[2]翟广玉,马海英,郜蕾.槲皮素及其衍生物的抗肿瘤活性研究进展[J].化学试剂,2015,37(2):97-103.
[3]AKIRA M,HITOSHI A,JUNJI T.Multitargeted cancer prevention by quercetin[J].Cancer Lett.,2008,269(2):315-325.
[4]FEDERICO D.Life or death:neuroprotective and anticancer effects of quercetin[J].J.Ethnopharmacol.,2012,143(2):383-396.
[5]DHARAMBIR K,SONAM M,KATRIN S,et al.Molecular mechanisms of action of quercetin in cancer:recent advances[J].Tumor Biol.,2016,37(10):12 927-12 939.
[6]EDWARDS R L,LYON T,LITWIN S E,et al.Quercetin reduces blood pressure in hypertensive subjects[J].J.Nutr.,2007,137(11):2 405-2 411.
[7]SHYAMALA G,ANDREA N F,ADAM T C,et al.Quercetin inhibits rhinovirus replication in vitro and in vivo[J].Antiviral Res.,2012,94(3):258-271.
[8]AGNES W B,GUIDO R M,ALT B.Health effects of quercetin:from antioxidant to nutraceutical[J].Eur.J.Pharmacol.,2008,585(2/3):325-337.
[9]VENGADESHPRABHU K,SOMASUNDARAM A,RAJARAJAN A T,et al.Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis[J].Drug Discov.Today,2016,21(4):632-639.
[10]EDISON O,EDWIN G P,CARLOS A,et al.Why is quercetin a better antioxidant than taxifolin?Theoretical study of mechanisms involving activated forms[J].J.Mol.Model,2013,19(6):2 165-2 172.
[11]ALKA G,KAVITA B,INDIRA R,et al.Quercetin:a wonder bioflavonoid with therapeutic potential in disease management[J].Asian Pac.J.Trop.Dis.,2016,6(3):248-252.
[12]VANESA A M,GABRIELA V F,MATIAS I S,et al.Spectroscopic and thermodynamic study of chrysin and quercetin complexes with Cu(Ⅱ)[J].J.Chem.Eng.Data,2016,61(2):987-995.
[13]HUANG He,JIA Qi,MA Jin-gui,et al.Discovering novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors[J].Eur.J.Med.Chem.,2009,44(5):1 982-1 988.
[14]WANG Xiao-lan,DUAN Yu.Anti-platelet aggregation mechanisms of quercetin fatty acid ester[J].J.Chem.Pharm.Res.,2014,6(6):599-602.
[15]NATASA M,MARTIN S,MARCELA K,et al.Modulation of BV-2 microglia functions by novel quercetin pivaloyl ester[J].Neurochem.Int.,2015,90:246-254.
[16]SATVIR S L,ZIAULLAH Z,VASANTHA H P,et al.Novel quercetin-3-O-glucoside eicosapentaenoic acid ester,ameliorates inflammation and hyperlipidemia[J].Inflammopharmacol,2015,23(4):173-185.
[17]PANAGIOTIS T N,PARASKEVI T,ANASTASIOS P,et al.Novel polyfunctional esters of ibuprofen and ketoprofen with hypolipidemic,lipoxygenase inhibitory and enhanced anti-inflammatory activity[J].Med.Chem.Res.,2017,26(2):461-472.
[18]TAHSIN F K,MARIA V C,MIN-SUNG L E,et al.Rational design and structure-activity relationship studies of quercetin-amino acid hybrids targeting the anti-apoptotic protein Bcl-x L[J].Org.Biomol.Chem.,2017,15(37):7 956-7 976.
[19]MARTINA Z,TEODOR A E,VLADIM K,et al.Effect of3-O-Galloyl substitution on the electrochemical oxidation of quercetin and silybin galloyl esters at glassy carbon electrode[J].Electroanal,2013,25(7):1 621-1 627.
[20]YE Bin,YANG Jin-liang,CHEN Li-juan,et al.Induction of apoptosis by phenylisocyanate derivative of quercetin:involvement of heat shock protein[J].Anti-Cancer Drugs,2007,18(10):1 165-1 171.
[21]SAMOKHVALOV G I,BUDAGYANTS M I,SHAKHOVAM K,et al.7-Alkyl ethers of quercetin and their antioxidant efficiency[J].Russ.Chem.Bull.,1963,12(9):1 475-1 478.
[22]BOUKTAIB M,ATMANI A,ROLANDO C.Regio-and stereoselcetive synthesis of the major metabolite of quercetin,quercetin-3-O-beta-D-glucuronide[J].Tetrahedron Lett.,2002,43(35):6 263-6 266.
[23]EKTA K,HANUMANTHARAO G R,RANJU K,et al.Comparison of the prevention of aflatoxin B1-induced genotoxicity by quercetin and quercetin pentaacetate[J].Bioorg.Med.Chem.Lett.,2002,12(18):2 579-2 582.