Research progress in structural modification and pharmacological activities of berberine

JIN Xin; SONG Xia; CAO Yongbin; JIANG Yuanying; SUN Qingyan

doi:10.3969/j.issn.1006-0111.2014.03.003

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2014 > 32(3): 171-175

JIN Xin, SONG Xia, CAO Yongbin, JIANG Yuanying, SUN Qingyan. Research progress in structural modification and pharmacological activities of berberine[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(3): 171-175. doi: 10.3969/j.issn.1006-0111.2014.03.003

Citation:

JIN Xin, SONG Xia, CAO Yongbin, JIANG Yuanying, SUN Qingyan. Research progress in structural modification and pharmacological activities of berberine[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(3): 171-175. doi: 10.3969/j.issn.1006-0111.2014.03.003

Research progress in structural modification and pharmacological activities of berberine

doi: 10.3969/j.issn.1006-0111.2014.03.003

1.
Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China;Second Military Medical University, Shanghai 200433, China
2.
Second Military Medical University, Shanghai 200433, China

Received Date: 2013-09-24
Rev Recd Date: 2014-02-24

Abstract

Berberine was an isoquinoline type alkaloid extracted from Chinese herbs such as Coptis chinensis. Recently, as a great many berberine derivatives had been synthesized with comprehensive physiological functions, the structural modification and application of berberine showed great promising significance. Recent literatures had been systematically analyzed and summarized in this review. With abundant pharmacological activities of berberine different sites'derivatives had been presented, systematical information of berberine structural modification as a lead compound and new drug R&D were provided in this article.
- berberine derivates,
- structure-function relationship,
- pharmacological activities

References

[1]	濮礼班,许翔鸿,张宇和,等.黄连生长状况及生物碱含量的个体差异[J].中草药,1999,30(5):375-377.
[2]	张韶湘,邹澄,赵庆,等.小檗碱衙生物的合成及药理活性研究[J].中国民族民间医药杂志,2007,86(03):167-186.
[3]	林云,张灿,华维一.原小檗碱类化合物的构效关系研究进展[J].药学进展,2002,26(2):76-80.
[4]	刘欣荣.天然药物小檗碱的临床用途[J].光明中医,2007,22(8):73-75.
[5]	李波,朱维良,陈凯先.小檗碱及其衍生物的研究进展[J].药学学报,2008,43(8):773-787.
[6]	Li YH,Yang P,Kong WJ,et al.Berberine analogues as a novel class of the low-density lipoprotein receptor up-regulators:synthesis,structure,activity relationships,and cholesterol,lowering efficacy[J].J Med Chem,2009, 52(2): 492-501.
[7]	Yang Y,Ye XL,Li XG,et al.Synthesis and antimicrobial activity of 8-alkylberberine derivatives with a long aliphatic chain[J].Planta Med,2007,73(6): 602-604.
[8]	Cheng Z,Chen AF,Wu F,et al.8,8-dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models[J].Bioorg Med Chem,2010,18(16): 5915-5924.
[9]	西南大学.8-辛基小檗碱盐酸盐、合成方法及应用[P].中国,CN1974569A,2007-06-06.
[10]	Bustanji Y,Taha MO,Yousef AM,et al.Berberine potently inhibits protein tyrosine phosphatase 1B: investigation by docking simulation and experimental validation[J].J Enzyme Inhib Med Chem,2006,21(2): 163-171.
[11]	Wang YX,Fu HG,Li YH,et al.Synthesis and biological evaluation of 8-substituted berberine derivatives as novel anti-mycobacterial agents[J].Acta Pharmaceut Sinica B,2012,2(6): 581-587.
[12]	Hoshi A,Ikekawa T,Ikeda Y,et al.Antitumor activity of berberrubine derivatives[J].Gann, 1976,67(2): 321-325.
[13]	Ma Y,Ou TM,Hou JQ,et al.9-N-substituted berberine derivatives:stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc[J].Bioorg Med Chem,2008,16(16):7582-7591.
[14]	Lo CY, Hsu LC,Chen MS,et al.Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives:a lipophilic substitute role[J].Bioorg Med Chem Lett,2013,23(1):305-309.
[15]	Pang JY,Qin Y,Chen WH,et al.Synthesis and DNA-binding affinities of monomodified berberines[J].Bioorg Med Chem,2005,13(20):5835-5840.
[16]	Chen WH,Pang JY,Qin Y,et al.Synthesis of linked berberine dimers and their remarkably enhanced DNA-binding affinities[J].Bioorg Med Chem Lett,2005,15(10):2689-2692.
[17]	Zhang WJ,Ou TM,Lu YJ,et al.9-substituted berberine derivatives as G-quadruplex stabilizing ligands in telomeric DNA[J].Bioorg Med Chem,2007,15(16):5493-5501.
[18]	Ma Y,Ou TM,Hou JQ,et al.9-N-substituted berberine derivatives: stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc[J].Bioorg Med Chem,2008,16(16):7582-7591.
[19]	Ma Y,Ou TM,Tan JH,et al.Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands[J].Bioorg Med Chem Lett,2009,19(13):3414-3417.
[20]	Basu A,Jaisankar P,Suresh KG,et al.Synthesis of novel 9-O-N-aryl/aryl-alkyl amino carbonyl methyl substituted berberine analogs and evaluation of DNA binding aspects[J].Bioorg Med Chem,2012,20(8):2498-2505.
[21]	Ma Y,Huang ZSh.Synthesis and activity evaluation of 9-O-substituted berberine derivatives containing polyamine Chain as highly selective telomeric G-quadruplex stabilizing ligands[J].Chem J Chin Univ, 2012,33(10):2217-2222.
[22]	Li QY,Zu YG,Liu TY,et al.Generation of reactive oxygen species by a novel berberine-bile acid analog mediates apoptosis in hepatocarcinoma SMMC-7721 cells[J].Biochem Biophys Res Commun,2013,433(4):432-437.
[23]	Kim SH,Lee SJ,Lee JH,et al.Antimicrobial activity of 9-O-acyl-and 9-O-alkylberberrubine derivatives[J].Planta Med,2002,68(3):277-281.
[24]	Hong SW,Kim SH,Jeun JA,et al.Antimicrobial activity of 9-O-acyl-and 9-O-benzoyl-substituted berberrubines[J].Planta Med,2000,66(4):361-363.
[25]	Huang L,Shi A,He F,et al.Synthesis,biological evaluation,and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors[J].Bioorg Med Chem,2010,18(3):1244-1251.
[26]	Huang L,Luo Z,He F,et al.Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase[J].Bioorg Med Chem,2010,18(12):4475-4484.
[27]	Shan WJ,Huang L,Zhou Q,et al.Synthesis,biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant,inhibitors of acetylcholinesterase,butyrylcholinesterase and amyloid-β aggregation[J].Eur J Med Chem,2011,46(12):5885-5893.
[28]	Shi AD,Huang L,Lu CJ,et al.Synthesis,biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and beta-amyloid aggregation inhibitors[J].Bioorg Med Chem,2011,19(7):2298-2305.
[29]	Chen Zh,Ye XL,Yi J,et al.Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation[J].Med Chem Res,2012,21(8):1641-1646.
[30]	Li YH,Li Y,Yang P,et al.Design,synthesis,and cholesterol-lowering efficacy for prodrugs of berberrubine[J].Bioorg Med Chem,2010,18(17):6422-6428.
[31]	Bodiwala HS,Sabde S,Mitra D,et al.Synthesis of 9-substituted derivatives of berberine as anti-HIV agents[J].Eur J Med Chem,2011,46(4):1045-1049.
[32]	Franceschin M,Rossetti L,D'Ambrosio A,et al.Natural and synthetic G-quadruplex interactive berberine derivatives[J].Bioorg Med Chem Lett,2006,16(6):1707-1711.
[33]	Gornall KC,Samosom S,Talib J,et al.Selectivity of an indolyl berberine derivative for tetrameric G-quadruplex DNA[J].Rapid Commun Mass Spectrom,2007,21(11):1759-1766.
[34]	Ball AR,Casadei G,Samosorn S,et al.Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial[J].ACS Chem Biol,2006,1(9):594-600.
[35]	Samosorn S,Tanwirat B,Muhamad N,et al.Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group[J].Bioorg Med Chem,2009,17(11):3866-3872.
[36]	Park KD,Lee JH,Kim SH,et al.Synthesis of 13-(substituted benzyl) berberine and berberrubine derivatives as antifungal agents[J].Bioorg Med Chem Lett,2006,16(15):3913-3916.
[37]	Liu YX,Xiao CL,Wang YX,et al.Synthesis,structure-activity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberberine derivatives[J].Eur J Med Chem,2012,52:151-158.
[38]	Iwasa K,Nishiyama Y,Ichmiaru M,et al.Structure activity relationship of quaternary protoberberine alkaloids havnig antimlaarial activity[J].Eur J Med Chem,1999,34:1077-1083.
[39]	Park KD,Cho SJ,Moon JS,et al.Synthesis and antifungal activity of a novel series of 13-(4-isopropylbenzyl)berberine derivatives[J].Bioorg Med Chem Lett,2010,20(22):6551-6554.
[40]	Iwasa K,Lee DU,Kang SI,et al.Antimicrobial activity of 8-alkyl-and 8-phenyl-substituted berberines and their 12-bromo derivatives[J].Nat Prod,1998,61(9):1150-1153.
[41]	Kim JH.Pharmaceutically available protoberberine salts deriva-tives and protoberberine salte derivative,and protoberberin deriv-atives and salts thereof[P].US,008356.1999-12-28.
[42]	中国科学院上海药物研究所.13,13a-二氢小檗碱衍生物及其药物组合物和用途[P].中国,CN101153039A.2008-04-02.
[43]	Bahar M,Deng Y,Zhu X,et al.Potent antiprotozoal activity of a novel semi-synthetic berberine derivative[J].Bioorg Med Chem Lett,2011,21(9):2606-2610.
[44]	Beausoleil E,Chauvignac C,Taverne T,et al.Structure-activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding[J].Bioorg Med Chem Lett,2009,19(19):5594-5598.

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通讯作者: 陈斌, [email protected]

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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Research progress in structural modification and pharmacological activities of berberine

1. Fujian University of Traditional Chinese Medicine, Fuzhou 350108, China;Second Military Medical University, Shanghai 200433, China

2. Second Military Medical University, Shanghai 200433, China

Received Date: 2013-09-24

Rev Recd Date: 2014-02-24

Key words:

Abstract: Berberine was an isoquinoline type alkaloid extracted from Chinese herbs such as Coptis chinensis. Recently, as a great many berberine derivatives had been synthesized with comprehensive physiological functions, the structural modification and application of berberine showed great promising significance. Recent literatures had been systematically analyzed and summarized in this review. With abundant pharmacological activities of berberine different sites'derivatives had been presented, systematical information of berberine structural modification as a lead compound and new drug R&D were provided in this article.

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Reference (44)

[1]	濮礼班,许翔鸿,张宇和,等.黄连生长状况及生物碱含量的个体差异[J].中草药,1999,30(5):375-377.
[2]	张韶湘,邹澄,赵庆,等.小檗碱衙生物的合成及药理活性研究[J].中国民族民间医药杂志,2007,86(03):167-186.
[3]	林云,张灿,华维一.原小檗碱类化合物的构效关系研究进展[J].药学进展,2002,26(2):76-80.
[4]	刘欣荣.天然药物小檗碱的临床用途[J].光明中医,2007,22(8):73-75.
[5]	李波,朱维良,陈凯先.小檗碱及其衍生物的研究进展[J].药学学报,2008,43(8):773-787.
[6]	Li YH,Yang P,Kong WJ,et al.Berberine analogues as a novel class of the low-density lipoprotein receptor up-regulators:synthesis,structure,activity relationships,and cholesterol,lowering efficacy[J].J Med Chem,2009, 52(2): 492-501.
[7]	Yang Y,Ye XL,Li XG,et al.Synthesis and antimicrobial activity of 8-alkylberberine derivatives with a long aliphatic chain[J].Planta Med,2007,73(6): 602-604.
[8]	Cheng Z,Chen AF,Wu F,et al.8,8-dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models[J].Bioorg Med Chem,2010,18(16): 5915-5924.
[9]	西南大学.8-辛基小檗碱盐酸盐、合成方法及应用[P].中国,CN1974569A,2007-06-06.
[10]	Bustanji Y,Taha MO,Yousef AM,et al.Berberine potently inhibits protein tyrosine phosphatase 1B: investigation by docking simulation and experimental validation[J].J Enzyme Inhib Med Chem,2006,21(2): 163-171.
[11]	Wang YX,Fu HG,Li YH,et al.Synthesis and biological evaluation of 8-substituted berberine derivatives as novel anti-mycobacterial agents[J].Acta Pharmaceut Sinica B,2012,2(6): 581-587.
[12]	Hoshi A,Ikekawa T,Ikeda Y,et al.Antitumor activity of berberrubine derivatives[J].Gann, 1976,67(2): 321-325.
[13]	Ma Y,Ou TM,Hou JQ,et al.9-N-substituted berberine derivatives:stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc[J].Bioorg Med Chem,2008,16(16):7582-7591.
[14]	Lo CY, Hsu LC,Chen MS,et al.Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives:a lipophilic substitute role[J].Bioorg Med Chem Lett,2013,23(1):305-309.
[15]	Pang JY,Qin Y,Chen WH,et al.Synthesis and DNA-binding affinities of monomodified berberines[J].Bioorg Med Chem,2005,13(20):5835-5840.
[16]	Chen WH,Pang JY,Qin Y,et al.Synthesis of linked berberine dimers and their remarkably enhanced DNA-binding affinities[J].Bioorg Med Chem Lett,2005,15(10):2689-2692.
[17]	Zhang WJ,Ou TM,Lu YJ,et al.9-substituted berberine derivatives as G-quadruplex stabilizing ligands in telomeric DNA[J].Bioorg Med Chem,2007,15(16):5493-5501.
[18]	Ma Y,Ou TM,Hou JQ,et al.9-N-substituted berberine derivatives: stabilization of G-quadruplex DNA and down-regulation of oncogene c-myc[J].Bioorg Med Chem,2008,16(16):7582-7591.
[19]	Ma Y,Ou TM,Tan JH,et al.Synthesis and evaluation of 9-O-substituted berberine derivatives containing aza-aromatic terminal group as highly selective telomeric G-quadruplex stabilizing ligands[J].Bioorg Med Chem Lett,2009,19(13):3414-3417.
[20]	Basu A,Jaisankar P,Suresh KG,et al.Synthesis of novel 9-O-N-aryl/aryl-alkyl amino carbonyl methyl substituted berberine analogs and evaluation of DNA binding aspects[J].Bioorg Med Chem,2012,20(8):2498-2505.
[21]	Ma Y,Huang ZSh.Synthesis and activity evaluation of 9-O-substituted berberine derivatives containing polyamine Chain as highly selective telomeric G-quadruplex stabilizing ligands[J].Chem J Chin Univ, 2012,33(10):2217-2222.
[22]	Li QY,Zu YG,Liu TY,et al.Generation of reactive oxygen species by a novel berberine-bile acid analog mediates apoptosis in hepatocarcinoma SMMC-7721 cells[J].Biochem Biophys Res Commun,2013,433(4):432-437.
[23]	Kim SH,Lee SJ,Lee JH,et al.Antimicrobial activity of 9-O-acyl-and 9-O-alkylberberrubine derivatives[J].Planta Med,2002,68(3):277-281.
[24]	Hong SW,Kim SH,Jeun JA,et al.Antimicrobial activity of 9-O-acyl-and 9-O-benzoyl-substituted berberrubines[J].Planta Med,2000,66(4):361-363.
[25]	Huang L,Shi A,He F,et al.Synthesis,biological evaluation,and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors[J].Bioorg Med Chem,2010,18(3):1244-1251.
[26]	Huang L,Luo Z,He F,et al.Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase[J].Bioorg Med Chem,2010,18(12):4475-4484.
[27]	Shan WJ,Huang L,Zhou Q,et al.Synthesis,biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant,inhibitors of acetylcholinesterase,butyrylcholinesterase and amyloid-β aggregation[J].Eur J Med Chem,2011,46(12):5885-5893.
[28]	Shi AD,Huang L,Lu CJ,et al.Synthesis,biological evaluation and molecular modeling of novel triazole-containing berberine derivatives as acetylcholinesterase and beta-amyloid aggregation inhibitors[J].Bioorg Med Chem,2011,19(7):2298-2305.
[29]	Chen Zh,Ye XL,Yi J,et al.Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation[J].Med Chem Res,2012,21(8):1641-1646.
[30]	Li YH,Li Y,Yang P,et al.Design,synthesis,and cholesterol-lowering efficacy for prodrugs of berberrubine[J].Bioorg Med Chem,2010,18(17):6422-6428.
[31]	Bodiwala HS,Sabde S,Mitra D,et al.Synthesis of 9-substituted derivatives of berberine as anti-HIV agents[J].Eur J Med Chem,2011,46(4):1045-1049.
[32]	Franceschin M,Rossetti L,D'Ambrosio A,et al.Natural and synthetic G-quadruplex interactive berberine derivatives[J].Bioorg Med Chem Lett,2006,16(6):1707-1711.
[33]	Gornall KC,Samosom S,Talib J,et al.Selectivity of an indolyl berberine derivative for tetrameric G-quadruplex DNA[J].Rapid Commun Mass Spectrom,2007,21(11):1759-1766.
[34]	Ball AR,Casadei G,Samosorn S,et al.Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial[J].ACS Chem Biol,2006,1(9):594-600.
[35]	Samosorn S,Tanwirat B,Muhamad N,et al.Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group[J].Bioorg Med Chem,2009,17(11):3866-3872.
[36]	Park KD,Lee JH,Kim SH,et al.Synthesis of 13-(substituted benzyl) berberine and berberrubine derivatives as antifungal agents[J].Bioorg Med Chem Lett,2006,16(15):3913-3916.
[37]	Liu YX,Xiao CL,Wang YX,et al.Synthesis,structure-activity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberberine derivatives[J].Eur J Med Chem,2012,52:151-158.
[38]	Iwasa K,Nishiyama Y,Ichmiaru M,et al.Structure activity relationship of quaternary protoberberine alkaloids havnig antimlaarial activity[J].Eur J Med Chem,1999,34:1077-1083.
[39]	Park KD,Cho SJ,Moon JS,et al.Synthesis and antifungal activity of a novel series of 13-(4-isopropylbenzyl)berberine derivatives[J].Bioorg Med Chem Lett,2010,20(22):6551-6554.
[40]	Iwasa K,Lee DU,Kang SI,et al.Antimicrobial activity of 8-alkyl-and 8-phenyl-substituted berberines and their 12-bromo derivatives[J].Nat Prod,1998,61(9):1150-1153.
[41]	Kim JH.Pharmaceutically available protoberberine salts deriva-tives and protoberberine salte derivative,and protoberberin deriv-atives and salts thereof[P].US,008356.1999-12-28.
[42]	中国科学院上海药物研究所.13,13a-二氢小檗碱衍生物及其药物组合物和用途[P].中国,CN101153039A.2008-04-02.
[43]	Bahar M,Deng Y,Zhu X,et al.Potent antiprotozoal activity of a novel semi-synthetic berberine derivative[J].Bioorg Med Chem Lett,2011,21(9):2606-2610.
[44]	Beausoleil E,Chauvignac C,Taverne T,et al.Structure-activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding[J].Bioorg Med Chem Lett,2009,19(19):5594-5598.

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Research progress in structural modification and pharmacological activities of berberine

doi: 10.3969/j.issn.1006-0111.2014.03.003

Abstract

References

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通讯作者: 陈斌, [email protected]

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