川芎嗪的结构修饰及生物活性研究进展
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摘要
川芎嗪(Tetramethylpyrazine,TMPZ)是从伞形科植物中药川芎中提取的化学单体,具有改善心脑血管疾病的作用。现代药理学研究表明,TMPZ具有抗血小板凝聚、抗氧化应激、扩张细小动脉和提高心脑器官血流量等生物活性,但在临床应用中却面临代谢快、生物利用度低等问题。目前基于TMPZ代谢特点而进行的化学结构改造主要集中在酯类、酮类、哌嗪类、烃类及高分子聚合类等化合物。本文对TMPZ的化学结构修饰及其生物活性研究进行综述,为TMPZ的深入研究和临床合理应用提供参考。
Tetramethylpyrazine(TMPZ),a pure component from Chuanxiong Rhizoma(scientific name:Ligusticum chuanxiong Hort)., presents potential benefits to cardiovascular and cerebrovascular diseases. TMPZ has various promising biological activities such as anti-platelet-aggregation, dilating arterioles, increasing cardiovascular and cerebrovascular blood flow,and anti-oxidative stress. However,high metabolic rate and low bioavailability of TMPZ in human body is found in clinical application. Main derivatives of TMPZ include esters, ketones, piperazines,hydrocarbons and polymer compounds. This article reviews the progress of chemical structure modification of TMPZ and bioactivities of new derivatives,to provide reference for its future research and clinical practice.
Tetramethylpyrazine(TMPZ),a pure component from Chuanxiong Rhizoma(scientific name:Ligusticum chuanxiong Hort)., presents potential benefits to cardiovascular and cerebrovascular diseases. TMPZ has various promising biological activities such as anti-platelet-aggregation, dilating arterioles, increasing cardiovascular and cerebrovascular blood flow,and anti-oxidative stress. However,high metabolic rate and low bioavailability of TMPZ in human body is found in clinical application. Main derivatives of TMPZ include esters, ketones, piperazines,hydrocarbons and polymer compounds. This article reviews the progress of chemical structure modification of TMPZ and bioactivities of new derivatives,to provide reference for its future research and clinical practice.
引文
[1]北京制药工业研究所.川芎Ⅰ号碱(川芎嗪)技术鉴定会报道[J].医药工业,1977,8(Z1):55-56.
[2]GUO M,LIU Y,SHI D.Cardiovascular actions and therapeutic potential of tetramethylpyrazine(active component isolated from rhizoma chuanxiong):roles and mechanisms[J].Biomed Research International,2016,2016:2430329.
[3]江骥,胡蓓,李晓明,等.人体内川芎嗪药代动力学参数的稳定同位素法测定[J].中国药学杂志,1994,29(7):416-418.
[4]江骥,姜国辉,叶云鹏,等.川芎嗪的体内代谢[J].中国医学科学院学报,1993,15(2):79-82.
[5]高芸.川芎嗪的不良反应综述[J].现代中西医结合杂志,2008,17(18):2901-2903.
[6]NIE S Q,MAJARAIS I,KWAN C Y,et al.Analogues of tetramethylpyrazine affect membrane fluidity of liposomes:relationship to their biological activities[J].European Journal of Pharmacology Molecular Pharmacology,1994,266(1):11-18.
[7]陈学敏,谢人明,郑旭光,等.川芎嗪氮上取代对血小板聚集性的影响[J].西北药学杂志,2001,16(4):164-166.
[8]边晓丽,陈学敏,刘艳霞,等.川芎嗪及其衍生物对羟自由基的清除作用[J].中国医院药学杂志,2003,23(11):678-679.
[9]刘新泳,徐文方,张蕊,等.川芎醇酯类衍生物及其制备方法和含有川芎醇酯类衍生物的药物组合物与应用:中国,ZL02135989X[P].2005-01-12.
[10]LIU X Y,ZHANG R,XU W F,et al.Synthesis of the novel liqustrazine derivatives and their protective effect on injured vascular endothelial cell damaged by hydrogen peroxide[J].Bioorganic&Medicinal Chemistry Letters,2003,34(42):2123-2126.
[11]赵丽霞,郭秀丽,刘新泳.川芎嗪烟酸酯对神经细胞氧化损伤的保护作用[J].中国药学杂志,2006,41(6):420-423.
[12]王鹏.川芎嗪结构修饰及生物活性测定甘氨酸茶碱纳缓释片不对称给药的药代动力学研究[D].沈阳:沈阳药科大学,2003.
[13]刘建建.川芎嗪衍生物的设计、合成及其生物活性研究[D].济南:山东大学,2006.
[14]丁倩,崔磊,矫春晓,等.川芎嗪肉桂酰类双酯衍生物对内皮细胞氧化损伤的保护作用[J].潍坊医学院学报,2009,31(6):426-428.
[15]SUN Y,JIANG J,ZHANG Z,et al.Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke[J].Bioorganic&Medicinal Chemistry,2008,16(19):8868-8874.
[16]李沙,王磊,陈海南,等.川芎嗪硝酮衍生物在大鼠体内的组织分布研[J].中国临床药理学杂志,2011,27(1):42-45.
[17]许长林,单璐琛,孙业伟,等.川芎嗪衍生物TBN对家兔血小板聚集性的影响[J].中药材,2010,33(9):1450-1453.
[18]陈智,刘继红,尹春萍,等.川芎嗪对家兔阴茎海绵体平滑肌细胞游离钙浓度的影响[J].中华男科学杂质志,2003,9(5):331-334.
[19]肖恒军,刘继红,尹春萍,等.川芎嗪对离体兔阴茎海绵体平滑肌条收缩的影响[J].中华实验外科杂志,2004,21(8):964-965.
[20]张立冬.川芎嗪衍生物合成及抗ED药理活性研究[D].武汉:华中科技大学,2008.
[21]张立冬,刘继红,李邃,等.川芎嗪衍生物对人阴茎海绵体平滑肌细胞游离钙浓度的影响[J].医药导报,2009,28(2):148-150.
[22]叶云鹏.川芎嗪的代谢转化和结构改造的研究[D].北京:中国协和医科大学,1993.
[23]陈洪飞.川芎嗪新型衍生物的设计、合成及其生物活性研究[D].济南:山东大学,2010.
[24]CHEN H F,LI G N,ZHAN P,et al.Ligustrazine derivatives.Part5:design,synthesis and biological evaluation of novel ligustrazinyloxy-cinnamic acid derivatives as potent cardiovascular agents[J].European Journal of Medicinal Chemistry,2011,46(11):5609-5615.
[25]陈洪飞.新型凝血因子Xa抑制剂和川芎嗪衍生物的设计、合成及心脑血管活性研究[D].济南:山东大学,2014.
[26]程先超,刘新泳,徐文方.川芎嗪的结构改造及修饰[J].药学进展,2005,29(6):241-246.
[27]程先超.川芎嗪衍生物的设计、合成及其心脑血管药理活性研究[D].济南:山东大学,2005.
[28]CHENG X C,LIU X Y,XU W F,et al.Ligustrazine derivatives.Part 3:design,synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents[J].Bioorganic&Medicinal Chemistry,2009,17(8):3018-3024.
[29]程先超,刘新泳,徐文方,等.川芎嗪二苯甲基哌嗪衍生物对ECV-304细胞氧化损伤的保护作用[J].山东大学学报(医学版),2007,45(9):931-933.
[30]薛鹏,吕国凯,程先超,等.川芎嗪哌嗪衍生物的合成与表征[J].化学试剂,2006,28(9):513-514,569.
[31]OU Y,GUO X L,ZHAI L,et al.TMPDP,a tetramethylpyrazine derivative,protects vascular endothelial cells from oxidation damage by hydrogen peroxide[J].Die Pharmazie,2010,65(10):755-759.
[32]冯永红,许实波.白藜芦醇药理作用研究进展[J].国外医药(植物药分册),1996,11(4):155-157.
[33]刘华臣,董爱君,高春梅,等.白藜芦醇结构修饰及药理活性[J].化学进展,2009,21(8):1500-1506.
[34]邓利娟.川芎嗪茋类衍生物的设计、合成及其生物活性研究[D].济南:山东大学,2007.
[35]DENG L,GUO X,LI Z,et al.Ligustrazine derivatives.Part 4:design,synthesis,and biological evaluation of novel ligustrazinebased stilbene derivatives as potential cardiovascular agents[J].Chemical Biology&Drug Design,2012,79(5):731-739.
[36]张爽.川芎嗪代谢产物及其衍生物的设计、合成与生物活性研究[D].济南:山东大学,2012.
[37]李家明,赵永海,马逢时,等.川芎嗪芳酸衍生物的合成及抗血小板聚集活性[J].有机化学,2008,28(9):1578-1583.
[38]王兴坡,刘新泳,于恒斌.2-二苯胺甲基-3,5,6-三甲基吡嗪的合成[J].华西药学杂志,2000,15(5):360-361.
[39]刘新泳,葛蔚颖,徐丽君,等.川芎嗪体内代谢产物的合成[J].山东医科大学学报,1997,35(1):80.
[40]夏承建,王松,朱鹤孙.聚乙二醇二酸(2-羟甲基-3,5,6-三甲基吡嗪)酯的合成及其体外降解性能[J].精细化工,2004,21(9):676-678.
[41]林妮妮,王松,朱鹤孙.川芎嗪及其衍生物的抗凝血活性研究[C].2004年材料科学与工程新进展(2004年中国材料研讨会会议论文集).北京:冶金工业出版社,2004:303-307.
[42]姜国辉.核技术在新药研究中的应用[D].北京:中国协和医科大学,1994.
[43]唐刚华,姜国辉,王世真,等.阿魏酸盐的合成及药理作用研究[J].中国药学杂志,1999,34(10):697-699.
[44]陈海南,李沙,王兴立,等.大鼠静脉注射川芎嗪体内药动学研究[J].中药材,2010,33(10):1599-1602.
[45]刘晓勤,楼雅卿,陈清棠.正常人及缺血性脑血管病病人的盐酸川芎嗪临床药代动力学研究[J].中国临床药理学杂志,1991,7(1):32-36.
[46]XU D M,WU D.Protective effect of ligustrazine hydrochloride on homocysteine-injured ECV304 cells[J].China Journal of Chinese Materia Medica,2012,37(12):1836-1839.
[47]赵玉清,笔雪艳.磷酸川芎嗪注射液药理毒理研究综述[J].时珍国医国药,2007,18(7):1780-1781.
[48]杨杰.川芎嗪的结构修饰及生物活性实验研究[D].西安:陕西师范大学,2003.
[2]GUO M,LIU Y,SHI D.Cardiovascular actions and therapeutic potential of tetramethylpyrazine(active component isolated from rhizoma chuanxiong):roles and mechanisms[J].Biomed Research International,2016,2016:2430329.
[3]江骥,胡蓓,李晓明,等.人体内川芎嗪药代动力学参数的稳定同位素法测定[J].中国药学杂志,1994,29(7):416-418.
[4]江骥,姜国辉,叶云鹏,等.川芎嗪的体内代谢[J].中国医学科学院学报,1993,15(2):79-82.
[5]高芸.川芎嗪的不良反应综述[J].现代中西医结合杂志,2008,17(18):2901-2903.
[6]NIE S Q,MAJARAIS I,KWAN C Y,et al.Analogues of tetramethylpyrazine affect membrane fluidity of liposomes:relationship to their biological activities[J].European Journal of Pharmacology Molecular Pharmacology,1994,266(1):11-18.
[7]陈学敏,谢人明,郑旭光,等.川芎嗪氮上取代对血小板聚集性的影响[J].西北药学杂志,2001,16(4):164-166.
[8]边晓丽,陈学敏,刘艳霞,等.川芎嗪及其衍生物对羟自由基的清除作用[J].中国医院药学杂志,2003,23(11):678-679.
[9]刘新泳,徐文方,张蕊,等.川芎醇酯类衍生物及其制备方法和含有川芎醇酯类衍生物的药物组合物与应用:中国,ZL02135989X[P].2005-01-12.
[10]LIU X Y,ZHANG R,XU W F,et al.Synthesis of the novel liqustrazine derivatives and their protective effect on injured vascular endothelial cell damaged by hydrogen peroxide[J].Bioorganic&Medicinal Chemistry Letters,2003,34(42):2123-2126.
[11]赵丽霞,郭秀丽,刘新泳.川芎嗪烟酸酯对神经细胞氧化损伤的保护作用[J].中国药学杂志,2006,41(6):420-423.
[12]王鹏.川芎嗪结构修饰及生物活性测定甘氨酸茶碱纳缓释片不对称给药的药代动力学研究[D].沈阳:沈阳药科大学,2003.
[13]刘建建.川芎嗪衍生物的设计、合成及其生物活性研究[D].济南:山东大学,2006.
[14]丁倩,崔磊,矫春晓,等.川芎嗪肉桂酰类双酯衍生物对内皮细胞氧化损伤的保护作用[J].潍坊医学院学报,2009,31(6):426-428.
[15]SUN Y,JIANG J,ZHANG Z,et al.Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke[J].Bioorganic&Medicinal Chemistry,2008,16(19):8868-8874.
[16]李沙,王磊,陈海南,等.川芎嗪硝酮衍生物在大鼠体内的组织分布研[J].中国临床药理学杂志,2011,27(1):42-45.
[17]许长林,单璐琛,孙业伟,等.川芎嗪衍生物TBN对家兔血小板聚集性的影响[J].中药材,2010,33(9):1450-1453.
[18]陈智,刘继红,尹春萍,等.川芎嗪对家兔阴茎海绵体平滑肌细胞游离钙浓度的影响[J].中华男科学杂质志,2003,9(5):331-334.
[19]肖恒军,刘继红,尹春萍,等.川芎嗪对离体兔阴茎海绵体平滑肌条收缩的影响[J].中华实验外科杂志,2004,21(8):964-965.
[20]张立冬.川芎嗪衍生物合成及抗ED药理活性研究[D].武汉:华中科技大学,2008.
[21]张立冬,刘继红,李邃,等.川芎嗪衍生物对人阴茎海绵体平滑肌细胞游离钙浓度的影响[J].医药导报,2009,28(2):148-150.
[22]叶云鹏.川芎嗪的代谢转化和结构改造的研究[D].北京:中国协和医科大学,1993.
[23]陈洪飞.川芎嗪新型衍生物的设计、合成及其生物活性研究[D].济南:山东大学,2010.
[24]CHEN H F,LI G N,ZHAN P,et al.Ligustrazine derivatives.Part5:design,synthesis and biological evaluation of novel ligustrazinyloxy-cinnamic acid derivatives as potent cardiovascular agents[J].European Journal of Medicinal Chemistry,2011,46(11):5609-5615.
[25]陈洪飞.新型凝血因子Xa抑制剂和川芎嗪衍生物的设计、合成及心脑血管活性研究[D].济南:山东大学,2014.
[26]程先超,刘新泳,徐文方.川芎嗪的结构改造及修饰[J].药学进展,2005,29(6):241-246.
[27]程先超.川芎嗪衍生物的设计、合成及其心脑血管药理活性研究[D].济南:山东大学,2005.
[28]CHENG X C,LIU X Y,XU W F,et al.Ligustrazine derivatives.Part 3:design,synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents[J].Bioorganic&Medicinal Chemistry,2009,17(8):3018-3024.
[29]程先超,刘新泳,徐文方,等.川芎嗪二苯甲基哌嗪衍生物对ECV-304细胞氧化损伤的保护作用[J].山东大学学报(医学版),2007,45(9):931-933.
[30]薛鹏,吕国凯,程先超,等.川芎嗪哌嗪衍生物的合成与表征[J].化学试剂,2006,28(9):513-514,569.
[31]OU Y,GUO X L,ZHAI L,et al.TMPDP,a tetramethylpyrazine derivative,protects vascular endothelial cells from oxidation damage by hydrogen peroxide[J].Die Pharmazie,2010,65(10):755-759.
[32]冯永红,许实波.白藜芦醇药理作用研究进展[J].国外医药(植物药分册),1996,11(4):155-157.
[33]刘华臣,董爱君,高春梅,等.白藜芦醇结构修饰及药理活性[J].化学进展,2009,21(8):1500-1506.
[34]邓利娟.川芎嗪茋类衍生物的设计、合成及其生物活性研究[D].济南:山东大学,2007.
[35]DENG L,GUO X,LI Z,et al.Ligustrazine derivatives.Part 4:design,synthesis,and biological evaluation of novel ligustrazinebased stilbene derivatives as potential cardiovascular agents[J].Chemical Biology&Drug Design,2012,79(5):731-739.
[36]张爽.川芎嗪代谢产物及其衍生物的设计、合成与生物活性研究[D].济南:山东大学,2012.
[37]李家明,赵永海,马逢时,等.川芎嗪芳酸衍生物的合成及抗血小板聚集活性[J].有机化学,2008,28(9):1578-1583.
[38]王兴坡,刘新泳,于恒斌.2-二苯胺甲基-3,5,6-三甲基吡嗪的合成[J].华西药学杂志,2000,15(5):360-361.
[39]刘新泳,葛蔚颖,徐丽君,等.川芎嗪体内代谢产物的合成[J].山东医科大学学报,1997,35(1):80.
[40]夏承建,王松,朱鹤孙.聚乙二醇二酸(2-羟甲基-3,5,6-三甲基吡嗪)酯的合成及其体外降解性能[J].精细化工,2004,21(9):676-678.
[41]林妮妮,王松,朱鹤孙.川芎嗪及其衍生物的抗凝血活性研究[C].2004年材料科学与工程新进展(2004年中国材料研讨会会议论文集).北京:冶金工业出版社,2004:303-307.
[42]姜国辉.核技术在新药研究中的应用[D].北京:中国协和医科大学,1994.
[43]唐刚华,姜国辉,王世真,等.阿魏酸盐的合成及药理作用研究[J].中国药学杂志,1999,34(10):697-699.
[44]陈海南,李沙,王兴立,等.大鼠静脉注射川芎嗪体内药动学研究[J].中药材,2010,33(10):1599-1602.
[45]刘晓勤,楼雅卿,陈清棠.正常人及缺血性脑血管病病人的盐酸川芎嗪临床药代动力学研究[J].中国临床药理学杂志,1991,7(1):32-36.
[46]XU D M,WU D.Protective effect of ligustrazine hydrochloride on homocysteine-injured ECV304 cells[J].China Journal of Chinese Materia Medica,2012,37(12):1836-1839.
[47]赵玉清,笔雪艳.磷酸川芎嗪注射液药理毒理研究综述[J].时珍国医国药,2007,18(7):1780-1781.
[48]杨杰.川芎嗪的结构修饰及生物活性实验研究[D].西安:陕西师范大学,2003.