具有抗肿瘤活性的槲皮素衍生物研究进展
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摘要
槲皮素是黄酮类天然产物,具有多种药理活性,近年来其优良的抗肿瘤活性受到了国内外学者的关注,但由于特殊的分子结构导致其水溶性较差,影响了其临床应用价值,因此对其结构进行化学修饰以改善生物利用度或提高抗肿瘤活性成为了研究的热点。对近年来具有抗肿瘤活性的槲皮素酯类衍生物、金属配合物、醚类衍生物及其他衍生物的研究进展进行综述,以期为槲皮素抗肿瘤新药的开发提供科学依据。
Quercetin, as a natural product of flavonoids, has many pharmacological activities, and its excellent antitumor activity has been concerned by many scholars at home and abroad in recent years. However, quercetin is poorly water-soluble because of its special molecular structure, which affects its medicinal value in clinic. Therefore, the chemical modification of its structure to improve its bioavailability or antitumor activity has become a hot research topic. In this paper, recent advances in the study of quercetin derivatives with anticancer activity, such as quercetin ester derivatives, metal complexes, ether derivatives, and other derivatives are reviewed, which provides scientific basis for the future development of antitumor drugs from quercetin.
Quercetin, as a natural product of flavonoids, has many pharmacological activities, and its excellent antitumor activity has been concerned by many scholars at home and abroad in recent years. However, quercetin is poorly water-soluble because of its special molecular structure, which affects its medicinal value in clinic. Therefore, the chemical modification of its structure to improve its bioavailability or antitumor activity has become a hot research topic. In this paper, recent advances in the study of quercetin derivatives with anticancer activity, such as quercetin ester derivatives, metal complexes, ether derivatives, and other derivatives are reviewed, which provides scientific basis for the future development of antitumor drugs from quercetin.
引文
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[6]Wong M Y,Chiu G N.Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen receptor negative breast cancer treatment[J].Anti-Cancer Drugs,2010,21(4):401-410.
[7]Zheng S Y,Li Y,Jiang D,et al.Anticancer effect and apoptosis induction by quercetin in the human lung cancer cell line A-549[J].Mol Med Report,2012,5(3):822-826.
[8]Pietta P G.Flavonoids as antioxidants[J].J Nat Prod,2000,63(7):1035-1042.
[9]Ferry D R,Smith A,Malkhandi J,et al.Phase I clinical trial of the flavonoid quercetin:Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition[J].Clin Cancer Res,1996,2(4):659-680.
[10]孟德胜,汪仕良.槲皮素的抗癌作用[J].中草药,2001,32(2):186-188.
[11]Murakmi A,Ashida H,Terao J.Multitargeted cancer prevention by quercetin[J].Cancer Lett,2008,269(2):315-325.
[12]Daja F.Life or death:Neuroprotective and anticancer effects of quercetin[J].J Ethnopharmacol,2012,143(2):383-396.
[13]Mendoza E E,Burdr R.Quercetin as a systemic chemopreventative agent:Structural and functional mechanisms[J].Mini Rev Med Chem,2011,11(14):1216-1221.
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[15]Vargas A J,Burd R.Hormesis and synergy:Pathways and mechanisms of quercetin in cancer prevention and management[J].Nutr Rev,2010,68(7):418-428.
[16]Hirpara K V,Aggarwal P,Mukherjee A J,et al.Quercetin and its derivatives:Synthesis,pharmacological uses with special emphasis on antitumor properties and prodrug with enhanced bioavailability[J].Anticancer Agents MedChem,2009,9(2):138-161.
[17]Lamson D W,Brignall M S.Antioxidants and cancer,Part3:Quercetin[J].Altern Med Rev,2000,5(3):196-208.
[18]Gibellini L,Pinti M,Nasi M,et al.Quercetin and cancer chemoprevention,evidence-based complementary and alter native medicine[J].Nutr Cancer,2011,59(1):18-32.
[19]Chen C,Zhou J,Ji C Y.Quercetin:a potential drug to reverse multidrug resistance[J].Life Sci,2010,87(11/12):333-338.
[20]红宇,韩艳秋.槲皮素抗肿瘤及抗氧化作用的研究进展[J].中华临床医师杂志,2012,6(15):4409-4411.
[21]王刚,杜士,杨光义.槲皮素抗肿瘤的分子机制研究进展[J].中国医院药学杂志,2011,31(4):322-324.
[22]孙铁民,孙长山,戴光渊,等.一种槲皮素衍生物在制备抗肿瘤药物中的应用[J].中国药物化学杂志,2003,13(6):345-348.
[23]Mulholland P J,Ferry D R,Anderson D,et al.Proclinical and clinical study of QCl2,a water-soluble,prodrug of quercetin[J].Ann Oncol,2001,12(2):245-248.
[24]Golding B T,Griffin R J,Quarterman C P.et al.Analogues or derivatives of quercetin:WO,9749693A[P].1997-06-27.
[25]Calias P,Galanopoulos T,Maxwell M,et al.Synthesis of inositol 2-phosphate-quercetin conjugates[J].CarbohydRes,1996,292(3):83-90.
[26]叶斌.槲皮索苯基异氰酸酯抗肿瘤实验研究[D].成都:四川大学,2006.
[27]Ye B,Yang J L,Chen L J,et al.Induction of apoptosis by phenylisocyanate derivative of quercetin:Involvement of heat shock protein[J].Anti-Cancer Drugs,2007,18(10):1165-1171.
[28]丁冶春,刘宗亮,徐仙赟,等.槲皮素-3-硫酸酯钠的合成、表征及抗肿瘤活性研究[J].赣南医学院学报,2012,32(1):16-18.
[29]朱玮.槲皮素酯类衍生物的合成及生物活性研究[D].郑州:郑州大学,2012.
[30]谭君,王伯初,祝连彩.槲皮素金属配合物的药理作用研究进展[J].中国药学杂志,2006,41(22):1688-1691.
[31]Tan J,Wang B C,Zhu L C.DNA binding,cytotoxicity,apoptotic inducing activity,and molecular modeling study of quercetin zinc(Ⅱ)complex[J].Bioorg Med Chem,2009,17(2):614-620.
[32]Tan J,Zhu L C,Wang B C.From GC-rich DNA binding to the repression of surviving gene for quercetin nickel(Ⅱ)complex:Implications for cancer therapy[J].Bio Metals,2010,23(6):1075-1084.
[33]Tan J,Wang B C,Zhu L C.DNA binding and oxidative DNA damage induced by a quercetin copper(Ⅱ)complex:potential mechanism of its antitumor properties[J].J Biol Inorg Chem,2009,14(5):727-739.
[34]Tan J,Zhu L C,Wang B C.GC(guanine-cytosine)-selective DNA-binding and antitumor activity of a quercetin-manganese(Ⅱ)complex[J].Chem Biodivers,2011,8(8):1550-1559.
[35]方新华.槲皮素-锌抗肿瘤作用及对Hep G22的细胞凋亡诱导机制研究[J].浙江中医药大学学报,2010,34(3):309-311.
[36]陈小平.槲皮素合氨络铂抗癌药及其制备方法:中国,101177434A[P].2007-12-13.
[37]翟广玉,王鹏,王涛,等.槲皮素铂的合成:中国,101353339A[P].2008-09-16.
[38]Tabassum S,Zaki M,Afzal M,et al.New modulated design and synthesis of quercetin-Cu(Ⅱ)/Zn(Ⅱ)-Sn2(Ⅳ)scaffold as anticancer agents:In vitro DNA binding profile,DNA cleavage pathway and Topo-I activity[J].Dalton Trans,2013,27(42):10029-10041.
[39]Zhou J,Wang L F,Wang J Y,et al.Synthesis,characterization,antioxidative and antitumor activities of solid quercetin rare earth(III)complexes[J].J Inorg Biochem,2001,83(1):41-48.
[40]贾景景,郭中原,梁曜华,等.槲皮素衍生物的合成及其抗肿瘤活性研究[J].中国药学杂志,2016,51(23):2013-2017.
[41]颜子童.槲皮素醚类衍生物的合成及其抗菌和抗肿瘤活性研究[D].郑州:郑州大学,2014.
[42]Manthey J A,Guhrie N.Antiproliferative activities of citrus flavonoids against six human cancer cell lines[J].J Agric Food Chem,2002,50(21):5837-5843.
[43]翟广玉,颜子童,渠文涛,等.一种槲皮素衍生物在制备抗肿瘤药物中的应用:中国,103239437A[P].2013-08-14.
[44]Strazisar M,Mlakar V,Glavac D.The expression of COX-2,h TERT,MDM2,LATS2 and S100A2 in different types of non-small cell lung cancer(NSCLC)[J].Cell Mol Biol Lett,2009,14(3):442-456.
[45]Li J X,Zhu F,Lubet R A,et al.Quercetin-3-methyl ether inhibits lapatinib-sensitive and resistant breast cancer cell growth by inducing G2/M arrest and apoptosis[J].Mol Carcinogens,2012,52(2):134-143.
[46]Jian Y,Iris L K,Wong T J,et al.Synthesis of methylated quercetin derivatives and their reversal activities on P-gp-and BCRP-mediated multidrug resistance tumour cells[J].Eur J Med Chem,2012,doi:10.1016/j.ejmech.2012.05.026.
[47]田延科,孙伟霞,张景亮,等.槲皮素-3-O-乙酸酯的合成及在抗肿瘤方面的应用:中国,105503804A[P].2016-04-20.
[48]Veverka M,Dubaj T,Gallovi?J,et al.Cocrystals of quercetin:Synthesis,characterization,and screening of biological activity[J].Monatsh Chem,2015,doi:10.1007/s00706-014-1314-6.
[49]Zhang H S,Zhang M,Yu L H,et al.Antitumor activities of quercetin and quercetin-5’,8-disulfonate in human colon and breast cancer cell lines[J].Food Chem Toxicol,2012,50(5):1589-1599.
[50]Daskiewicz J B,Depeint F,Viornery L,et al.Effects of flavonoids on cell proliferation and caspase activation in a human colonic cell line HT29:An SAR study[J].J Med Chem,2005,48(8):2790-2804.
[2]Moskaug J,Carlsen H,Myhrstad M,et al.Molecular imaging of the biological effects of quercetin and quercetin-rich foods[J].Mech Ageing Dev,2004,125(4):315-324.
[3]Russo M,Spagnuolo C,Tedesco I,et al.The flavonoid quercetin in disease prevention and therapy:Facts and fancies[J].Biochem Pharmacol,2012,83(1):6-15.
[4]Bischoff S C.Quercetin:Potentials in the prevention and therapy of disease[J].Curr Opin Clin Nutr Metab Care,2008,11(6):733-740.
[5]Noori-Daloii M R,Momeny M,Yousefi M,et al.Multifaceted preventive effects of single agent quercetin on a human prostate adeno-carcinoma cell line(PC-3):Implications for nutritional transcriptomics and multi-target therapy[J].Med Oncol,2011,28(4):1395-1404.
[6]Wong M Y,Chiu G N.Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen receptor negative breast cancer treatment[J].Anti-Cancer Drugs,2010,21(4):401-410.
[7]Zheng S Y,Li Y,Jiang D,et al.Anticancer effect and apoptosis induction by quercetin in the human lung cancer cell line A-549[J].Mol Med Report,2012,5(3):822-826.
[8]Pietta P G.Flavonoids as antioxidants[J].J Nat Prod,2000,63(7):1035-1042.
[9]Ferry D R,Smith A,Malkhandi J,et al.Phase I clinical trial of the flavonoid quercetin:Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition[J].Clin Cancer Res,1996,2(4):659-680.
[10]孟德胜,汪仕良.槲皮素的抗癌作用[J].中草药,2001,32(2):186-188.
[11]Murakmi A,Ashida H,Terao J.Multitargeted cancer prevention by quercetin[J].Cancer Lett,2008,269(2):315-325.
[12]Daja F.Life or death:Neuroprotective and anticancer effects of quercetin[J].J Ethnopharmacol,2012,143(2):383-396.
[13]Mendoza E E,Burdr R.Quercetin as a systemic chemopreventative agent:Structural and functional mechanisms[J].Mini Rev Med Chem,2011,11(14):1216-1221.
[14]Jagtap S,Meganathan K,Wagh V,et al.Chemoprotective mechanism of the natural compounds,epigallocatechin-3-O-gallate,quercetin and curcumin against cancer and cardiovascular diseases[J].Curr Med Chem,2009,16(12):1451-1462.
[15]Vargas A J,Burd R.Hormesis and synergy:Pathways and mechanisms of quercetin in cancer prevention and management[J].Nutr Rev,2010,68(7):418-428.
[16]Hirpara K V,Aggarwal P,Mukherjee A J,et al.Quercetin and its derivatives:Synthesis,pharmacological uses with special emphasis on antitumor properties and prodrug with enhanced bioavailability[J].Anticancer Agents MedChem,2009,9(2):138-161.
[17]Lamson D W,Brignall M S.Antioxidants and cancer,Part3:Quercetin[J].Altern Med Rev,2000,5(3):196-208.
[18]Gibellini L,Pinti M,Nasi M,et al.Quercetin and cancer chemoprevention,evidence-based complementary and alter native medicine[J].Nutr Cancer,2011,59(1):18-32.
[19]Chen C,Zhou J,Ji C Y.Quercetin:a potential drug to reverse multidrug resistance[J].Life Sci,2010,87(11/12):333-338.
[20]红宇,韩艳秋.槲皮素抗肿瘤及抗氧化作用的研究进展[J].中华临床医师杂志,2012,6(15):4409-4411.
[21]王刚,杜士,杨光义.槲皮素抗肿瘤的分子机制研究进展[J].中国医院药学杂志,2011,31(4):322-324.
[22]孙铁民,孙长山,戴光渊,等.一种槲皮素衍生物在制备抗肿瘤药物中的应用[J].中国药物化学杂志,2003,13(6):345-348.
[23]Mulholland P J,Ferry D R,Anderson D,et al.Proclinical and clinical study of QCl2,a water-soluble,prodrug of quercetin[J].Ann Oncol,2001,12(2):245-248.
[24]Golding B T,Griffin R J,Quarterman C P.et al.Analogues or derivatives of quercetin:WO,9749693A[P].1997-06-27.
[25]Calias P,Galanopoulos T,Maxwell M,et al.Synthesis of inositol 2-phosphate-quercetin conjugates[J].CarbohydRes,1996,292(3):83-90.
[26]叶斌.槲皮索苯基异氰酸酯抗肿瘤实验研究[D].成都:四川大学,2006.
[27]Ye B,Yang J L,Chen L J,et al.Induction of apoptosis by phenylisocyanate derivative of quercetin:Involvement of heat shock protein[J].Anti-Cancer Drugs,2007,18(10):1165-1171.
[28]丁冶春,刘宗亮,徐仙赟,等.槲皮素-3-硫酸酯钠的合成、表征及抗肿瘤活性研究[J].赣南医学院学报,2012,32(1):16-18.
[29]朱玮.槲皮素酯类衍生物的合成及生物活性研究[D].郑州:郑州大学,2012.
[30]谭君,王伯初,祝连彩.槲皮素金属配合物的药理作用研究进展[J].中国药学杂志,2006,41(22):1688-1691.
[31]Tan J,Wang B C,Zhu L C.DNA binding,cytotoxicity,apoptotic inducing activity,and molecular modeling study of quercetin zinc(Ⅱ)complex[J].Bioorg Med Chem,2009,17(2):614-620.
[32]Tan J,Zhu L C,Wang B C.From GC-rich DNA binding to the repression of surviving gene for quercetin nickel(Ⅱ)complex:Implications for cancer therapy[J].Bio Metals,2010,23(6):1075-1084.
[33]Tan J,Wang B C,Zhu L C.DNA binding and oxidative DNA damage induced by a quercetin copper(Ⅱ)complex:potential mechanism of its antitumor properties[J].J Biol Inorg Chem,2009,14(5):727-739.
[34]Tan J,Zhu L C,Wang B C.GC(guanine-cytosine)-selective DNA-binding and antitumor activity of a quercetin-manganese(Ⅱ)complex[J].Chem Biodivers,2011,8(8):1550-1559.
[35]方新华.槲皮素-锌抗肿瘤作用及对Hep G22的细胞凋亡诱导机制研究[J].浙江中医药大学学报,2010,34(3):309-311.
[36]陈小平.槲皮素合氨络铂抗癌药及其制备方法:中国,101177434A[P].2007-12-13.
[37]翟广玉,王鹏,王涛,等.槲皮素铂的合成:中国,101353339A[P].2008-09-16.
[38]Tabassum S,Zaki M,Afzal M,et al.New modulated design and synthesis of quercetin-Cu(Ⅱ)/Zn(Ⅱ)-Sn2(Ⅳ)scaffold as anticancer agents:In vitro DNA binding profile,DNA cleavage pathway and Topo-I activity[J].Dalton Trans,2013,27(42):10029-10041.
[39]Zhou J,Wang L F,Wang J Y,et al.Synthesis,characterization,antioxidative and antitumor activities of solid quercetin rare earth(III)complexes[J].J Inorg Biochem,2001,83(1):41-48.
[40]贾景景,郭中原,梁曜华,等.槲皮素衍生物的合成及其抗肿瘤活性研究[J].中国药学杂志,2016,51(23):2013-2017.
[41]颜子童.槲皮素醚类衍生物的合成及其抗菌和抗肿瘤活性研究[D].郑州:郑州大学,2014.
[42]Manthey J A,Guhrie N.Antiproliferative activities of citrus flavonoids against six human cancer cell lines[J].J Agric Food Chem,2002,50(21):5837-5843.
[43]翟广玉,颜子童,渠文涛,等.一种槲皮素衍生物在制备抗肿瘤药物中的应用:中国,103239437A[P].2013-08-14.
[44]Strazisar M,Mlakar V,Glavac D.The expression of COX-2,h TERT,MDM2,LATS2 and S100A2 in different types of non-small cell lung cancer(NSCLC)[J].Cell Mol Biol Lett,2009,14(3):442-456.
[45]Li J X,Zhu F,Lubet R A,et al.Quercetin-3-methyl ether inhibits lapatinib-sensitive and resistant breast cancer cell growth by inducing G2/M arrest and apoptosis[J].Mol Carcinogens,2012,52(2):134-143.
[46]Jian Y,Iris L K,Wong T J,et al.Synthesis of methylated quercetin derivatives and their reversal activities on P-gp-and BCRP-mediated multidrug resistance tumour cells[J].Eur J Med Chem,2012,doi:10.1016/j.ejmech.2012.05.026.
[47]田延科,孙伟霞,张景亮,等.槲皮素-3-O-乙酸酯的合成及在抗肿瘤方面的应用:中国,105503804A[P].2016-04-20.
[48]Veverka M,Dubaj T,Gallovi?J,et al.Cocrystals of quercetin:Synthesis,characterization,and screening of biological activity[J].Monatsh Chem,2015,doi:10.1007/s00706-014-1314-6.
[49]Zhang H S,Zhang M,Yu L H,et al.Antitumor activities of quercetin and quercetin-5’,8-disulfonate in human colon and breast cancer cell lines[J].Food Chem Toxicol,2012,50(5):1589-1599.
[50]Daskiewicz J B,Depeint F,Viornery L,et al.Effects of flavonoids on cell proliferation and caspase activation in a human colonic cell line HT29:An SAR study[J].J Med Chem,2005,48(8):2790-2804.